Association Between the VACS Index and NCI
Higher VACS Index scores were significantly associated with higher rates of global NCI (χ2 = 21.13, df = 1, P < 0.001, OR = 1.21, 95% CI: 1.12 to 1.32) and across all neurocognitive domains (Table 3).
When current mood symptoms was added as a predictor, the overall model was significant (χ2 = 33.89, df = 4, P < 0.001), and there continued to be a significant effect of the VACS Index (χ2 = 16.53, P < 0.001, OR = 1.20, 95% CI: 1.10 to 1.31) on global NCI. Worse depressive symptoms were also significantly associated with global NCI (χ2 = 14.43, P < 0.01). Similarly, after adjusting for mood symptoms the VACS Index remained significantly associated with all domains (P range < 0.001–0.04) except for verbal fluency (P = 0.16).
Analyses adjusting for lifetime substance use and major depressive disorders also showed a significant association between the VACS Index and global NCI (χ2 = 12.15, P < 0.001, OR = 1.19, 95% CI: 1.08 to 1.32), with neither lifetime history of a substance use disorder (P = 0.57) or major depressive disorder (P = 0.44) emerging as significant predictors. The VACS Index also continued to be significantly associated with all cognitive domains (P ranged from <0.01 to 0.02), except for learning (P = 0.06), when adjusting for substance use and major depressive disorders.
Analyses examining the effect of ART status (on/off) showed that the overall model was significant (χ2 = 27.75, df = 3, P < 0.001). Higher VACS Index scores and being on ART were associated with global NCI, but there was no significant interaction (Fig. 1). In models including nadir CD4 and estimated duration of infection, the VACS Index was significantly associated with global NCI (χ2 = 9.95, P < 0.01, OR = 1.18, 95% CI: 1.06 to 1.30), but neither of these other HIV-disease characteristics were significant (P > 0.13). Receiver-operating characteristic analyses showed that a VACS Index cutoff point of 18 maximized sensitivity (60%), whereas not compromising specificity beyond chance levels (50%). A cutoff point of 10 resulted in increased sensitivity (82%) but low specificity (26%). The ORs for a cutoff point of 18 and 10 were 1.54 (95% CI: 1.11 to 2.14) and 1.62 (95% CI: 1.08 to 2.44), respectively.
Association Between the Components of the VACS Index and Global NCI
Table 4 shows results from our multivariable stepwise regression on global NCI entering the VACS components as predictors. Our initial model including all VACS components showed that age was the only significant predictor. Plasma RNA, eGFR, FIB-4, and HCV were removed in that order given that they were not significantly associated with NCI (ie, had the highest P values). Our final model showed that older age was the strongest predictor, and lower current CD4 count and hemoglobin were also significantly associated with NCI.
To better characterize the association between the VACS Index and NCI, and because of the highly skewed distribution of the VACS Index, we divided our sample into 3 groups based on VACS Index scores (low VACS Index = lower quartile, n = 166; high VACS Index = upper quartile, n = 150; and medium VACS Index = between lower and upper quartile, n = 285). The χ2 tests showed that, although there were no significant differences on rates of NCI between the low (34.3% NCI) and medium (35.4% NCI) VACS Index groups (P = 0.81), the high VACS Index group was significantly different from both the low and medium groups (P < 0.001) and had nearly twice the frequency of NCI (57.3%) as the other groups. When adjusting these analyses for the same psychiatric and HIV characteristics presented above, the high VACS Index group remained significantly different from the other groups.
The VACS Index, which combines age, routinely obtained traditional HIV biomarkers, and common biomarkers of multiorgan system dysfunction, is predictive of mortality among those infected with HIV.3–6 This study adds to the current literature by showing that higher VACS Index scores are significantly associated with concurrent NCI in a large and well-characterized cohort of persons with HIV.
The association between the VACS Index and NCI was statistically significant for global cognition and all cognitive domains (ie, speed of information processing, verbal fluency, learning, recall, working memory, executive functioning, and motor skills) using neurocognitive scores adjusted for demographic characteristics (ie, age, education, gender, and ethnicity). This relation remained after controlling for psychiatric comorbidities (ie, current mood and history of depression and substance use disorder) for global NCI and most cognitive domains. Furthermore, ART status (on/off) did not significantly modify the association of the VACS Index with global NCI, and the VACS Index predicted NCI over and above other HIV-related characteristics (ie, nadir CD4 and estimated duration of infection). The rates of global NCI were almost double in participants with VACS Index scores in the upper quartile of our sample, when compared with those in lower quartiles. Taken together, these findings suggest that the VACS Index might be helpful in tracking the impact of HIV on NCI.
Importantly, the strength of the association between the VACS Index and NCI as measured by some of the domains was not particularly strong, and its classification accuracy for NCI was poor, casting doubt as to the clinical significance of our findings. Other factors not included in the VACS Index might improve its predictive utility for NCI, such as demographic factors (eg, ethnicity), non-HIV comorbidities (eg, cardiovascular disease markers), and HIV-related factors (eg, AIDS defining diagnoses). Furthermore, additional biomarkers might predict distinct cognitive outcomes and trajectories (eg, incident impairment, decline, and propensity for improvement). For instance, the accuracy of the VACS Index for NCI might improve with the addition of biomarkers of inflammation.46 The fibrin degradation product, D-dimer, is an indicator of inflammation and adds to the predictive accuracy of the VACS Index for mortality,4 as does soluble CD14, which is a marker of lipopolysaccharide-mediated monocyte activation and has also been associated with neurocognitive function.47 Although interleukin-6 might also be considered, it did not add to the predictive power of the VACS Index for mortality.4
The mechanism for the association between the VACS Index and NCI cannot be ascertained by our study, but our findings are consistent with the hypothesis that host factors (eg, age of the patient), traditional indicators of HIV-disease severity and markers of chronic diseases that frequently co-occur among HIV-infected persons might each play important roles in the clinical manifestation of cognitive impairment among HIV-infected individuals. Consistently, older age, lower hemoglobin levels and lower current CD4 counts were the better predictors of current NCI among all VACS components. Previous studies showed that separately all of these components are associated with HIV-associated NCI.19–21,23 In addition, in a study on a diverse group of HIV-infected adults,5 visual inspection of hazard ratios suggested that age, CD4, and hemoglobin were also the strongest predictors of mortality.
The fact that age showed the strongest association with NCI is consistent with prior findings.19,20 Notably, neurocognitive scores in our study were corrected for age, which raises the question as to whether age is capturing the effects of another variable associated with aging and HIV but not represented in the VACS Index, such as cerebrovascular disease. Alternatively, the normative corrections may not be optimal for this population or there may be interaction between aging and HIV that leads to worse neurocognitive outcomes. Consistent with prior research,23 anemia was also notably associated with NCI. Anemia is known to often reflect the impact of AIDS, immune activation, and malnutrition on the bone barrow and on red cell growth factors, such as erythropoietin, which is itself neuroprotective.
Our study has several limitations. Although we had a considerable range in VACS Index scores, we had a relatively small number of participants 65 years and older, with evidence of fibrosis, compromised renal function, and HCV coinfection. Moreover, most of our sample was male. Follow-up analyses showed that the association between the VACS Index and NCI was somewhat stronger in our subgroup of participants 50+ years (n = 108, P = 0.01, OR = 1.36, 95% CI: 1.06 to 1.82), suggesting studies including older samples with higher rates of comorbidities might find stronger associations between the VACS Index and NCI. Furthermore, they might yield other components of the VACS as more predictive of NCI. Given the cross-sectional and correlational nature of this study, we cannot ascribe directionality to our findings. Longitudinal studies examining the predictive accuracy of the VACS Index for incident NCI would be better suited to address causality. Although ART status and current mood symptoms were associated with NCI when included as covariates in separate models with the VACS Index, caution is warranted in the interpretation of these findings, as our study was not designed to examine these associations. The strength of our study is our comprehensive neurocognitive battery that is adjusted for demographics, is validated in persons with HIV, and is particularly sensitive to the impairments seen in this population.8,37 Furthermore, it measures cognitive domains with composite scores, which are more reliable and valid than using single tests for the assessment of neurocognitive deficits, and is being used internationally in studies of HIV.48
Future studies examining whether other biomarkers not included in the VACS Index might enhance its relation to neurocognition would help improve the index as a tool to track the clinical manifestation of neuro-AIDS. Components in the current form of the VACS Index are weighted according to risk of all-cause mortality. We chose to keep these weightings because the purpose of our study was to evaluate the VACS Index in its current form and facilitate comparison with findings from other studies. Using a different weighting of VACS Index factors might strengthen its association with NCI. Given the documented association between NCI and real-world functional outcomes, an important next step will be to directly examine the relation between the VACS Index and everyday functioning outcomes relevant to HIV infection, such as medication adherence and employment.
Overall, we have found initial evidence linking the VACS Index with an important patient outcome in HIV, namely NCI. Although using a single VACS Index cutoff point poorly classified individuals as neurocognitively impaired, participants with VACS Index scores in the highest quartile were nearly twice as likely to be impaired than those in the lower quartile. If replicated, the VACS Index may be a simple tool for helping HIV practitioners identify HIV-infected patients who are at high risk for NCI and may warrant more comprehensive neurocognitive testing. Furthermore, as the VACS Index continues to be improved as a means of tracking disease burden in HIV, its relation to NCI might strengthen and further increase its utility in identifying individuals at risk for HIV-associated NCI.
The San Diego HNRC group is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the Veterans Affairs San Diego Healthcare System, and includes the following: Director: Robert K. Heaton, PhD, Co-Director: Igor Grant, MD; Associate Directors: J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, and Scott Letendre, MD; Center Manager: Thomas D. Marcotte, PhD; Jennifer Marquie-Beck, MPH; Melanie Sherman; Neuromedical Component: Ronald J. Ellis, MD, PhD (PI), Scott Letendre, MD, J. Allen McCutchan, MD, Brookie Best, PharmD, Rachel Schrier, PhD, Terry Alexander, RN, Debra Rosario, MPH; Neurobehavioral Component: Robert K. Heaton, PhD (PI), J. Hampton Atkinson, MD, Steven Paul Woods, PsyD, Thomas D. Marcotte, PhD, Mariana Cherner, PhD, David J. Moore, PhD, Matthew Dawson; Neuroimaging Component: Christine Fennema-Notestine, PhD (PI), John Hesselink, MD, Sarah L. Archibald, MA, Gregory Brown, PhD, Anders Dale, PhD, Thomas Liu, PhD; Neurobiology Component: Eliezer Masliah, MD (PI); Neurovirology Component: David M. Smith, MD (PI); International Component: J. Allen McCutchan, MD, (PI), Mariana Cherner, PhD; Developmental Component: Cristian Achim, MD, PhD; (PI), Stuart Lipton, MD, PhD; Participant Accrual and Retention Unit: J. Hampton Atkinson, MD (PI), Jennifer Marquie-Beck, MPH; Data Management and Information Systems Unit: Anthony C. Gamst, PhD (PI), Clint Cushman; Statistics Unit: Ian Abramson, PhD (PI), Florin Vaida, PhD (Co-PI), Reena Deutsch, PhD, Anya Umlauf, MS, Christi Kao, MS.
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Keywords:© 2014 by Lippincott Williams & Wilkins
HIV; comorbidity; cognition; cohort study; aging; anemia