1. Introduction
Current antiretroviral treatments have enabled the control of Human Immunodeficiency Virus (HIV) infection, suppressing viral load with drugs that are easy to administer and have few adverse effects. Since the introduction of highly active antiretroviral therapy, mortality among people living with HIV (PLHIV) has decreased, mainly due to a reduction in Acquired Immunodeficiency Syndrome (AIDS)-related mortality. However, a lower life expectancy persists among PLHIV in developed countries due to an increase in non-AIDS-related deaths, especially from non-related malignancies, and cardiovascular or respiratory events [
1,
2,
3,
4].
Life expectancy is no longer viral-dependent and is more related to organ damages and associated comorbidities. Therefore, specific risk indexes have been developed over the years that integrate biomarkers of organ function and comorbidity indexes. Two of the most used ones are the Veterans Aging Cohort Study (VACS) Index and the Charlson Comorbidity Index (CCI). Both have been applied in adult cohorts and offer mortality risk predictions but differ in their included variables and construction [
5]. The VACS Index was developed with health data from the VACS cohort and is based on routinely obtained HIV markers and non-HIV biomarkers of organ injury (
Appendix A) [
6]. It has demonstrated excellent 5-year mortality predictions, as seen in the NA-ACCORD collaboration [
7], and has been validated in different cohorts in America and Europe. The VACS Index has been improved with the addition of albumin, white blood cell count (WBC), and body mass index (BMI) in VACS 2.0 [
7,
8]. While VACS 2.0 offers enhanced discrimination, its components may not be universally available in all clinical databases, especially in historical data. Therefore, the simpler VACS 1.0 index could have broader applicability if its predictive value remains robust in contemporary cohorts. The Charlson Comorbidity Index (CCI) is an older instrument and was developed for the general population. It weights different diseases and comorbidities based on diagnostic codes in order to estimate long-term mortality, including 10-year mortality. In PLHIV it has been used to characterize the global comorbidity burden. Since the CCI does not consider HIV markers nor the immunological status, its predictive power is more limited. The aim of this study is, therefore, to evaluate the utility and discrimination of VACS 1.0 and a modified CCI for predicting all-cause and cause-specific 5- and 10-year mortality in a large, population-based cohort of PLHIV in the modern era of antiretroviral therapy (ART).
4. Discussion
In this study of a large European population-based cohort, the VACS Index 1.0 proved to be a robust predictor of 5-year mortality, with discrimination superior to that of a modified Charlson Index. We observed a C-statistic of 0.759 for 5-year all-cause mortality, a value comparable to the original validation studies [
6]. However, this result must be interpreted with caution, as it was derived from a cohort that excluded over one-third (35.2%) of the total cohort population.
The finding that the excluded group was characterized by a higher baseline mortality, greater injection drug use, and irregular follow-up is critically important. The VACS Index is constructed from markers that require regular clinical engagement. Therefore, the study design has an inherent bias that selects for a more stable and likely healthier population, which probably results in an optimistic estimation of the index’s performance. The true predictive ability of the VACS in a real-world, unselected population is therefore likely lower than what we report. This finding itself highlights that prognostic models based on clinical data may systematically fail to capture risk in the most vulnerable population.
Our cohort represents a population-based sample, including all individuals receiving HIV care in the Balearic Islands. This confers several strengths, such as demographic diversity—including women and immigrants—and access to high-quality clinical data. The integration of electronic health records and centralized laboratory systems ensures robust documentation of comorbidities and substance use. Furthermore, the cohort benefits from extended follow-up, minimal losses, and adherence to quality control standards consistent with national and international guidelines. Deaths and losses to follow-up were cross-validated through national and regional sources, including the National Institute of Statistics (INE) and the Balearic Health Department, allowing for reliable classification of causes of death. Importantly, unlike other studies, no imputation methods were used; PLHIV lacking the laboratory data necessary for calculating the VACS Index were excluded from the primary analyses.
Overall mortality in PLHIV for whom VACS Index 1.0 could be calculated was 10.79 deaths per 1000 person-years, notably lower than that reported in the original VACS, and more closely resembled figures from the ART-CC cohort [
6,
8]. This discrepancy is partly explained by the recency of our data, which includes individuals initiating ART after 2015, an era marked by universal treatment guidelines and widespread use of integrase strand transfer inhibitors. For individuals starting ART during this period, the ART-CC cohort reported a mortality rate of 8.2 per 1000 person-years [
13]. The median VACS Index in our cohort was 16 points, mirroring that observed in the ART-CC validation study [
6].
VACS 1.0 demonstrated strong predictive performance for five-year mortality in our cohort, with clear stratification of survival curves by VACS score categories. The hazard ratio (HR) for five-year mortality was 1.44 (95% CI: 1.38–1.51), which is higher than the HRs reported in the original VACS [1.22 (1.21–1.249)] and the ART-CC validation cohort [1.32 (1.27–1.38)], although the overall discriminatory power (C-statistic) was similar or slightly lower. Discrimination was highest for HIV-related deaths, chronic liver disease, and non-HIV infections, consistent with prior studies [
6,
13]. Although the median VACS Index was significantly higher in PLHIV aged over 50 (median 24), and mortality was accordingly greater (7.9%), predictive accuracy in this age group was not superior—an observation also noted in the VACS and ART-CC cohorts [
6,
8]. The discriminative capacity of the VACS 1.0 Index improved over time, being notably higher between 2016 and 2023 (C-statistic: 0.791) compared to the earlier period (C-statistic: 0.696), particularly for HIV- and liver-related causes of death.
This finding may be attributed to limitations in the calibration and discrimination of the VACS Index in certain subpopulations, such as individuals with CD4 counts below 200 cells/μL and women—groups that have historically been underrepresented in validation studies, which have largely focused on predominantly male veteran cohorts [
7,
8]. Alternatively, this improvement may reflect enhancements in the completeness and accuracy of laboratory data collection in more recent years, both in our cohort and in others.
Although the VACS Index effectively reflects an individual’s current health status, it does not account for longitudinal changes or cumulative exposures to risk factors, which may be important for long-term mortality prediction. This limitation could explain the stronger index performance in predicting short-term rather than long-term mortality outcomes [
14].
Recent validation studies have demonstrated that the VACS Index 2.0 maintains robust discriminatory ability and calibration for predicting all-cause mortality in contemporary cohorts, particularly when applied to data from 2010 to 2018—a period marked by declining mortality rates and evolving clinical characteristics among PLHIV [
7,
13]. The incorporation of additional laboratory markers in the VACS Index 2.0 enhances its capacity to capture the effects of both HIV-related and non-HIV-related morbidity. This enhancement is increasingly pertinent as the aging PLHIV population faces a greater burden of comorbidities, which have become key determinants of mortality risk. Consequently, VACS 2.0 offers more accurate risk stratification and mortality probability estimates in recent years compared to older models that do not account for the emerging factors.
The predictive performance of VACS 1.0 diminished when assessing ten-year mortality. VACS 2.0, which incorporates additional variables such as albumin, white blood cell count, and body mass index, has demonstrated improved discrimination over longer follow-up periods, increasing the C-statistic from 0.776 to 0.805 in the VACS cohort and from 0.800 to 0.831 in ART-CC [
8]. VACS 2.0 also enhances mortality prediction for certain causes of death, including chronic pulmonary disease, and has shown improved performance particularly among PLHIV with suppressed HIV-1 RNA levels [
7].
The Charlson Comorbidity Index (CCI) is a widely used tool for estimating ten-year survival, incorporating patient age and comorbidities [
9]. In our cohort, the prevalence of conditions such as renal failure and cancer was similar to that observed in the original VACS population. However, we observed a lower prevalence of diabetes mellitus and a higher prevalence of chronic liver disease (23.8%) and chronic obstructive pulmonary disease (COPD, 12.8%) [
5]. In the study by McGinnis et al. [
5], comparing comorbidities and the CCI between HIV-positive and HIV-negative populations, only chronic liver disease was more common in those living with HIV. Notably, despite a comparable comorbidity burden, the overall Charlson score was higher among people living with HIV, largely due to the heavy weighting of AIDS in the original index (6 points). In our study, we used a modified Charlson Index adjusted the AIDS weight to 1, aligning it with other comorbidities, as supported by previous findings [
10], and in recognition of the reduced predictive accuracy observed when using the original scoring. McGinnis et al. also demonstrated that VACS 2.0 and a combined VACS-CCI provided superior prediction of ten-year mortality, although the latter has not been widely validated [
5]. In the general and HIV-positive populations, the VACS-CCI showed excellent discrimination (C-statistic = 0.81), and when applied to people living with HIV, it yielded a similar predictive performance to VACS 2.0 (C = 0.77), closely aligning with our findings (C = 0.76).
Observed and predicted deaths were generally well aligned across specific causes, with deviations primarily occurring in individuals with VACS scores of 41–50 (higher than predicted mortality) and those with scores ≥ 81 (lower observed mortality).
Limitations
The primary limitation of this study is the selection bias already discussed. A second limitation is the use of VACS 1.0 instead of VACS 2.0. We have framed this as a pragmatic choice; the lack of complete laboratory data (specifically albumin and WBC) for the historical cohort prevented the calculation of VACS 2.0. However, this reflects a real-world scenario in many clinical settings where only the components of VACS 1.0 are available. Thus, our study provides a valuable validation of the simpler index’s utility in a contemporary.