Veterans Aging Cohort Study (VACS) 1.0 Index

The Veterans Aging Cohort Study (VACS) 1.0 Index represents a significant advancement in prognostic medicine for individuals living with HIV. Developed through extensive research within the Veterans Health Administration, this index integrates both HIV-specific biomarkers and general health indicators to provide a comprehensive assessment of mortality risk. Unlike traditional prognostic tools that focus solely on HIV-related parameters, the VACS 1.0 Index recognizes that mortality in people living with HIV is influenced by a complex interplay of viral factors, immune function, and general health status.

The index emerged from the recognition that as antiretroviral therapy (ART) has transformed HIV from a fatal disease to a manageable chronic condition, the causes of mortality have shifted. While AIDS-defining illnesses remain important, non-AIDS-defining conditions such as cardiovascular disease, liver disease, kidney disease, and cancer have become increasingly significant contributors to mortality. The VACS 1.0 Index addresses this reality by incorporating biomarkers that reflect both HIV-specific and general health status.

Historical Context and Development

The Veterans Aging Cohort Study was initiated to better understand the health outcomes of veterans living with HIV, particularly as they age. The study enrolled thousands of veterans and followed them longitudinally, collecting comprehensive clinical and laboratory data. Through rigorous statistical analysis of this rich dataset, researchers identified key biomarkers that independently predicted mortality risk.

The development of the VACS 1.0 Index involved sophisticated statistical modeling techniques, including Cox proportional hazards regression analysis. Researchers examined numerous potential predictors, including demographic factors, HIV-specific markers, laboratory values, and comorbidities. Through this process, they identified the most parsimonious set of predictors that provided optimal predictive performance while remaining clinically practical.

The index was developed using data from the Veterans Health Administration, which provides care to a large and diverse population of individuals living with HIV. This population includes veterans from various backgrounds, socioeconomic statuses, and geographic regions, enhancing the generalizability of the findings. The study design allowed for careful consideration of confounding factors and adjustment for potential biases.

Components of the VACS 1.0 Index

Age

Age is one of the most powerful predictors of mortality in the VACS 1.0 Index, reflecting the universal impact of aging on health outcomes. The index assigns points based on age categories: individuals under 50 years receive 0 points, those aged 50-64 years receive 12 points, and those 65 years or older receive 27 points. This scoring reflects the exponential increase in mortality risk with advancing age, which is particularly relevant in the context of HIV, where aging may interact with chronic inflammation and immune activation to accelerate age-related processes.

The importance of age in the VACS 1.0 Index highlights the changing demographics of the HIV epidemic. As effective ART has extended life expectancy, people living with HIV are experiencing the health challenges associated with aging. These include increased risk of cardiovascular disease, cancer, cognitive decline, and frailty. The index recognizes that age-related comorbidities contribute significantly to mortality risk in this population.

CD4 Count

CD4 count remains a fundamental marker of immune function in people living with HIV. The VACS 1.0 Index assigns points based on CD4 count categories, with higher point values for lower CD4 counts. Individuals with CD4 counts of 500 cells/mm³ or higher receive 0 points, reflecting preserved immune function. Those with CD4 counts between 350-499 cells/mm³ or 200-349 cells/mm³ receive 6 points each, indicating moderate immune compromise.

More severe immune compromise is associated with substantially higher point values. CD4 counts between 100-199 cells/mm³ receive 10 points, while those between 50-99 cells/mm³ receive 28 points. The most severe category, CD4 counts below 50 cells/mm³, receives 29 points, reflecting the high risk of opportunistic infections and AIDS-defining illnesses associated with severe immunodeficiency.

The CD4 count component of the index reflects both the direct impact of immunodeficiency on mortality risk and the indirect effects through increased susceptibility to infections and malignancies. Even in the era of effective ART, CD4 count recovery may be incomplete in some individuals, and low CD4 counts remain associated with increased mortality risk.

HIV-1 RNA (Viral Load)

HIV-1 RNA level, commonly referred to as viral load, is a critical marker of viral replication and treatment response. The VACS 1.0 Index incorporates viral load as a predictor of mortality risk, with higher viral loads associated with increased risk. Individuals with HIV-1 RNA levels below 500 copies/mL receive 0 points, reflecting effective viral suppression. Those with levels between 500-99,999 copies/mL receive 7 points, while those with levels of 100,000 copies/mL or higher receive 14 points.

The viral load component reflects several important aspects of HIV care. First, it indicates the effectiveness of antiretroviral therapy, with higher viral loads potentially indicating treatment failure, poor adherence, or drug resistance. Second, higher viral loads are associated with increased immune activation and inflammation, which may contribute to non-AIDS-defining conditions. Third, viral load serves as a marker of disease progression risk, with higher levels associated with more rapid CD4 decline and increased risk of AIDS-defining illnesses.

In the modern era of HIV care, most individuals receiving effective ART achieve undetectable viral loads. However, the index recognizes that viral load remains an important predictor of mortality risk, particularly in individuals who have not achieved viral suppression or who experience virologic failure.

Hemoglobin

Hemoglobin level is included in the VACS 1.0 Index as a marker of general health status and anemia, which is common in people living with HIV. The index assigns points based on hemoglobin categories, with lower hemoglobin levels associated with higher point values. Individuals with hemoglobin levels of 14 g/dL or higher receive 0 points, reflecting normal hemoglobin levels. Those with levels between 12-13.9 g/dL receive 10 points, indicating mild anemia.

More severe anemia is associated with substantially higher point values. Hemoglobin levels between 10-11.9 g/dL receive 22 points, while levels below 10 g/dL receive 38 points, the highest point value for any single component in the index. This reflects the significant impact of severe anemia on mortality risk, which may be related to multiple factors including underlying disease processes, nutritional deficiencies, chronic inflammation, and bone marrow suppression.

Anemia in people living with HIV may result from various causes, including HIV itself, opportunistic infections, medications, nutritional deficiencies, and chronic kidney disease. The inclusion of hemoglobin in the index recognizes that anemia is not merely a symptom but a significant contributor to mortality risk, potentially through its effects on cardiovascular function, exercise capacity, and overall health status.

FIB-4 Index

The FIB-4 (Fibrosis-4) index is a non-invasive marker of liver fibrosis that combines age, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and platelet count. The VACS 1.0 Index incorporates FIB-4 as a predictor of mortality risk, recognizing the importance of liver disease in people living with HIV. Individuals with FIB-4 values below 1.45 receive 0 points, reflecting low risk of significant liver fibrosis. Those with values between 1.45-3.25 receive 6 points, while those with values above 3.25 receive 25 points.

Liver disease is a significant cause of morbidity and mortality in people living with HIV, particularly in those with hepatitis C virus (HCV) coinfection, hepatitis B virus (HBV) coinfection, or alcohol use. The FIB-4 index provides a practical way to assess liver fibrosis risk using readily available laboratory values, without requiring more invasive procedures such as liver biopsy.

The inclusion of FIB-4 in the VACS 1.0 Index reflects the recognition that liver disease contributes significantly to mortality risk in this population. Advanced liver fibrosis is associated with increased risk of liver failure, hepatocellular carcinoma, and complications of portal hypertension. The index recognizes that liver health is an important component of overall health status in people living with HIV.

Estimated Glomerular Filtration Rate (eGFR)

Kidney function, as measured by estimated glomerular filtration rate (eGFR), is a critical component of the VACS 1.0 Index. The index assigns points based on eGFR categories, with lower eGFR values associated with higher point values. Individuals with eGFR values above 60 mL/min/1.73m² receive 0 points, reflecting normal kidney function. Those with values between 45-59.9 mL/min/1.73m² receive 6 points, indicating mild kidney dysfunction.

More significant kidney dysfunction is associated with higher point values. eGFR values between 30-44.9 mL/min/1.73m² receive 8 points, while values below 30 mL/min/1.73m² receive 26 points, reflecting the high mortality risk associated with severe kidney dysfunction. This scoring recognizes that kidney disease is a significant contributor to mortality risk in people living with HIV, potentially through multiple mechanisms including cardiovascular disease, electrolyte imbalances, and complications of end-stage renal disease.

Kidney disease in people living with HIV may result from various causes, including HIV-associated nephropathy, medication toxicity, diabetes, hypertension, and HCV coinfection. The inclusion of eGFR in the index recognizes that kidney function is a critical determinant of health outcomes and that early detection and management of kidney disease may improve outcomes.

Hepatitis C Virus (HCV) Coinfection

Hepatitis C virus coinfection is included in the VACS 1.0 Index as a binary variable, with individuals having HCV coinfection receiving 5 additional points. This reflects the significant impact of HCV coinfection on mortality risk in people living with HIV. HCV coinfection is associated with increased risk of liver disease, including cirrhosis and hepatocellular carcinoma, as well as increased risk of certain non-AIDS-defining cancers and cardiovascular disease.

The inclusion of HCV coinfection as a separate component, in addition to FIB-4, recognizes that HCV coinfection has effects beyond those captured by liver fibrosis markers. HCV coinfection may contribute to chronic inflammation, immune activation, and metabolic abnormalities that increase mortality risk independently of liver disease severity.

In the modern era, effective direct-acting antiviral (DAA) therapy for HCV has transformed the prognosis of HCV coinfection. However, the index was developed during a time when HCV treatment was less effective and less widely available. The impact of HCV cure on VACS 1.0 Index scores and mortality risk is an area of ongoing research.

Calculation and Scoring

The VACS 1.0 Index is calculated by summing the points assigned to each component. The total score ranges from 0 to over 100 points, with higher scores indicating higher predicted mortality risk. The calculation is straightforward and can be performed using readily available clinical and laboratory data, making it practical for use in clinical settings.

To calculate the index, clinicians first determine the patient's age category and assign the corresponding points. Next, they obtain the most recent CD4 count and assign points based on the count category. The most recent HIV-1 RNA level is then used to assign points for viral load. Hemoglobin level from a recent complete blood count is used to assign points for anemia status.

The FIB-4 index must be calculated using the formula: FIB-4 = (Age × AST) / (Platelets × √ALT), where age is in years, AST and ALT are in U/L, and platelets are in 10⁹/L. The calculated FIB-4 value is then used to assign points. Similarly, eGFR must be calculated using a creatinine-based equation, such as the CKD-EPI equation, and the calculated value is used to assign points.

Finally, the presence or absence of HCV coinfection is determined, typically through HCV antibody and RNA testing, and 5 points are added if coinfection is present. All points are then summed to obtain the total VACS 1.0 Index score.

Risk Stratification

The VACS 1.0 Index score can be used to stratify patients into risk categories, which can guide clinical decision-making and resource allocation. While specific risk category thresholds may vary depending on the clinical context and population, common categorizations include:

• Low Risk: Scores less than 30 points indicate lower predicted mortality risk. These patients typically have well-controlled HIV, preserved immune function, and minimal comorbidities.
• Moderate Risk: Scores between 30-49 points indicate moderate predicted mortality risk. These patients may have some immune compromise, comorbidities, or other risk factors that warrant closer monitoring.
• High Risk: Scores between 50-74 points indicate high predicted mortality risk. These patients typically have significant immune compromise, multiple comorbidities, or other serious health issues that require intensive management.
• Very High Risk: Scores of 75 points or higher indicate very high predicted mortality risk. These patients often have severe immune compromise, advanced comorbidities, or other life-threatening conditions that require immediate and aggressive intervention.

It is important to recognize that these risk categories are not absolute and should be interpreted in the context of the individual patient's clinical situation. The index provides a quantitative estimate of mortality risk, but clinical judgment remains essential in applying this information to patient care.

Clinical Applications

Risk Stratification and Prognosis

The primary application of the VACS 1.0 Index is risk stratification and prognosis assessment. By providing a quantitative estimate of mortality risk, the index can help clinicians identify patients who may benefit from more intensive monitoring, earlier intervention, or specialized care. This is particularly valuable in resource-limited settings, where the index can help prioritize care for patients at highest risk.

The index can also facilitate discussions with patients and families about prognosis and care planning. By providing a concrete, evidence-based estimate of risk, the index can help patients and families understand their health status and make informed decisions about treatment goals and care preferences. This is particularly important in the context of advance care planning and goals of care discussions.

Treatment Optimization

The VACS 1.0 Index can guide treatment optimization by identifying modifiable risk factors. For example, patients with high viral loads may benefit from optimization of antiretroviral therapy, including assessment of adherence, drug interactions, and potential resistance. Patients with low CD4 counts may benefit from closer monitoring for opportunistic infections and consideration of prophylaxis when indicated.

Similarly, patients with anemia may benefit from evaluation and treatment of underlying causes, such as iron deficiency, vitamin B12 deficiency, or chronic disease. Patients with elevated FIB-4 values may benefit from hepatology consultation and consideration of liver disease management, including HCV treatment if applicable. Patients with decreased eGFR may benefit from nephrology consultation and optimization of medications to preserve kidney function.

Resource Allocation

In healthcare systems with limited resources, the VACS 1.0 Index can help guide resource allocation decisions. Patients with higher scores may benefit from more frequent monitoring, earlier specialist referrals, or more intensive care management. This can help ensure that limited resources are directed toward patients who are most likely to benefit from intervention.

The index can also inform decisions about care setting, with higher-risk patients potentially benefiting from more intensive care settings or more frequent follow-up. This is particularly relevant in the context of care coordination and case management, where the index can help identify patients who may benefit from additional support services.

Research and Quality Improvement

The VACS 1.0 Index has applications beyond individual patient care. In research settings, the index can be used to adjust for baseline risk when comparing outcomes between groups or evaluating interventions. This can help ensure that observed differences in outcomes are not simply due to differences in baseline risk.

In quality improvement initiatives, the index can be used to identify patient populations at high risk for poor outcomes, allowing for targeted interventions to improve care. The index can also be used to monitor trends in patient risk over time, providing insights into the effectiveness of care delivery and the impact of interventions.

Validation and Performance

The VACS 1.0 Index has been extensively validated in multiple cohorts and populations. The index was originally developed and validated using data from the Veterans Health Administration, which provides care to a large and diverse population of individuals living with HIV. Subsequent validation studies have confirmed the index's performance in other populations, including those in academic medical centers, community health centers, and international settings.

The index has demonstrated strong predictive performance, with area under the receiver operating characteristic curve (AUC) values typically ranging from 0.75 to 0.85, depending on the population and outcome being predicted. This level of performance is considered good to excellent for a prognostic tool and compares favorably with other mortality prediction models.

The index has been validated for prediction of both all-cause mortality and cause-specific mortality, including AIDS-related mortality and non-AIDS-related mortality. This reflects the index's ability to capture risk factors for both HIV-specific and general health outcomes.

Importantly, the index has also been validated for prediction of other health outcomes beyond mortality, including hospitalization, functional decline, and neurocognitive impairment. This suggests that the index captures broader aspects of health status that are relevant to multiple outcomes, not just mortality.

Integration with Clinical Care

The VACS 1.0 Index is designed to be integrated into routine clinical care, with calculation requiring only standard clinical and laboratory data that are typically available in HIV care settings. The index can be calculated at the point of care, allowing for immediate risk assessment and clinical decision-making.

Many electronic health record systems and clinical decision support tools now include the VACS 1.0 Index as a built-in calculator, making it even more accessible to clinicians. These tools can automatically calculate the index using available laboratory and clinical data, reducing the burden on clinicians and ensuring consistent calculation methods.

The index can be calculated at regular intervals, such as at each clinic visit or annually, to monitor changes in risk over time. This longitudinal assessment can provide valuable insights into disease progression, treatment response, and the impact of interventions. Changes in the index score over time may indicate improvement or worsening of health status, guiding adjustments to care plans.

Comparison with Other Prognostic Tools

The VACS 1.0 Index is one of several prognostic tools available for people living with HIV. Other tools include the VACS 2.0 Index, which incorporates additional biomarkers such as albumin, body mass index, and white blood cell count; the VACS-CCI, which combines VACS components with the Charlson Comorbidity Index; and disease-specific tools such as the Framingham Risk Score for cardiovascular disease.

Compared to simpler tools that focus solely on HIV-specific markers such as CD4 count and viral load, the VACS 1.0 Index provides more comprehensive risk assessment by incorporating general health biomarkers. This is particularly valuable in the modern era of HIV care, where non-AIDS-defining conditions contribute significantly to mortality risk.

Compared to more complex tools that require extensive data collection or specialized testing, the VACS 1.0 Index provides a good balance between comprehensiveness and practicality. The index uses readily available clinical and laboratory data, making it feasible for use in diverse clinical settings.

Limitations and Considerations

While the VACS 1.0 Index is a valuable tool, it is important to recognize its limitations. The index provides a quantitative estimate of mortality risk, but it cannot predict individual outcomes with certainty. Many factors beyond those included in the index may influence mortality risk, including social determinants of health, access to care, treatment adherence, and individual patient characteristics.

The index was developed using data from the Veterans Health Administration, and while it has been validated in other populations, its performance may vary in different settings. Factors such as population demographics, healthcare systems, and available treatments may influence the index's predictive performance.

The index does not account for all potential risk factors. For example, it does not include information about specific comorbidities beyond those captured by biomarkers, such as diabetes, hypertension, or cancer. It also does not include information about social factors, such as housing stability, food security, or social support, which may significantly influence health outcomes.

The index should be interpreted in the context of the individual patient's clinical situation. A high score does not necessarily mean that a patient will die, and a low score does not guarantee survival. Clinical judgment remains essential in applying the index to patient care, and the index should be used as a tool to inform, rather than replace, clinical decision-making.

The index reflects risk at a point in time and may change as the patient's health status changes. Regular recalculation of the index can help monitor changes in risk over time, but the index should not be used as the sole basis for treatment decisions without consideration of the patient's current clinical status and treatment response.

Future Directions

Research continues to refine and improve the VACS 1.0 Index and develop new prognostic tools for people living with HIV. Areas of active research include the incorporation of additional biomarkers, such as inflammatory markers, coagulation markers, and metabolic markers, which may provide additional predictive value.

There is also interest in developing dynamic prediction models that account for changes in risk factors over time, rather than relying solely on cross-sectional assessments. Such models could provide more accurate risk estimates by incorporating information about disease progression and treatment response.

The impact of modern HIV treatments, including newer antiretroviral medications and treatment strategies, on the index's performance is an area of ongoing research. As treatment options continue to improve, the relationship between risk factors and outcomes may evolve, potentially requiring updates to the index or development of new tools.

There is also interest in expanding the index's applications beyond mortality prediction to include prediction of other important outcomes, such as hospitalization, functional decline, and quality of life. Such expansions could make the index even more valuable for clinical care and research.

Practical Implementation

For clinicians interested in implementing the VACS 1.0 Index in their practice, several practical considerations are important. First, ensure that the necessary laboratory and clinical data are available and up-to-date. The index requires recent values for CD4 count, HIV-1 RNA, hemoglobin, liver function tests, platelet count, and creatinine for eGFR calculation.

Second, establish a process for regular calculation of the index, such as at each clinic visit or annually. This can help monitor changes in risk over time and identify patients who may benefit from intervention. Electronic health record systems or clinical decision support tools can facilitate this process.

Third, develop a workflow for responding to index results. This may include protocols for when to refer patients to specialists, when to intensify monitoring, or when to initiate advance care planning discussions. The specific response will depend on the clinical context and available resources.

Finally, ensure that the index is used as a tool to inform, rather than replace, clinical judgment. The index provides valuable information about mortality risk, but it should be interpreted in the context of the individual patient's clinical situation, preferences, and goals of care.