To the Editors:
There is an increasing contribution of non-AIDS events to morbidity and mortality in HIV-infected patients on antiretroviral therapy.1,2 Among HIV-infected patients with suppressed HIV viremia, a CD4 count <200 cells/mm3 is independently associated with higher AIDS and non-AIDS morbidity and mortality.3,4 Among HIV-infected patients, 10%–20% have a blunted immune reconstitution on antiretroviral therapy. Clinic factors associated with a low CD4 cell count despite viral suppression include older age, lower nadir CD4 count, and HCV infection.5–8 In 2011, 11% of HIV-infected adults with HIV viral suppression seen at the Ruth M Rothstein CORE center (Chicago, IL) had CD4 counts <200 cells/mm3. The Veterans Aging Cohort Study (VACS) index, which includes 7 variables: age, CD4 count, HIV-1 RNA, hemoglobin, FIB-4, eGFR, and hepatitis C status, has recently been validated as a reliable index to assess 5-year mortality risk in HIV patients, with a 10-point increase in the VACS score predicting a 10% increase in 5-year mortality.9,10 This study describes the distribution of VACS scores and correlates of high VACS scores among patients with undetectable HIV RNA comparing those with CD4 counts <200 cells/mm3 to those with CD4 counts ≥200 cells/mm3.
A cross-sectional electronic chart review was performed of 4847 HIV-infected adults who were active in care in 2011 at the Ruth M Rothstein CORE center (Chicago, IL). Active in care was defined as ≥1 clinic visit and ≥1 CD4 count and ≥1 HIV viral load measured in 2011 at the CORE center. In the subset of patients with undetectable HIV RNA (<75 copies/mL), we compared overall VACS scores and the proportion with high-risk VACS variables (>10 points) stratified by CD4 <200 cells/mm3 vs CD4 ≥200 cells/mm3. The VACS index includes age, CD4 count, HIV-1 RNA and laboratory measurements of hemoglobin, aspartate and alanine transaminase (AST, ALT), platelets, creatinine, and HCV status. Composite markers of liver and renal injury (FIB-4 and GFR) are computed. FIB-4 = [(years of age × AST)/(platelets in 100/L ×
)] is a validated indicator of liver fibrosis.9 We compared VACS index measures between those with CD4 ≥200 cells/mm3 to those with CD4 <200 cells/mm3 using χ2 tests for categorical variables and Kruskal–Wallis tests for nonnormally distributed continuous variables. All analyses were conducted using SAS version 9.2. The study was approved by the Cook County Health and Hospitals System Institutional Review Board.
Of 4847 patients, 3496 (73%) had undetectable HIV RNA and were included in the analysis. Median CD4 count was 448 (IQR, 304–624). Seventy-four percent were male, 62% were African American, 23% were Hispanic/Latino, and were 12% white. Median age was 47 years and 41% were 50 years or older. Three hundred seventy-seven (11%) patients had CD4 counts <200/mm3, and of these, 73% had CD4 count 100–199 cells/mm3. The VACS variables stratified by CD4 strata are shown in the table with CD4 point contributions to VACS shown in the footnote of Table 1. The mean VACS score was higher in patients with CD4 counts <200 cells/mm3 (37.07 vs 18.48; P < 0.0001) and remained higher even after CD4 counts were excluded from the total score for all patients (22.15 vs 15.23; P < 0.001). Patients with CD4 <200 were more likely to have hemoglobin <12 (20% vs 11%; P < 0.0001), FIB-4 >3.25 (11% vs 3%; P < 0.0001), and were more likely to be hepatitis C virus positive (22% vs 17%; P = 0.01) compared with patients with CD4 ≥200 cells/mm3. Patients with CD4 <200 cells/mm3 were equally likely to be older than 50 years (45% vs 40%; P = 0.09) and equally likely to have an eGFR <30 mL/min (2% vs 2%; P = 0.19) compared with patients with CD4 ≥200. The proportion of patients with high VACS scores of ≥50 was also higher in patients with low CD4 counts 28% vs 5%. Overall 2% of patients had VACS scores >70; 10% in CD4 <200 vs 2% in CD4 >200 groups.
In this study of 3496 HIV-infected patients with suppressed viremia, 11% had CD4 counts <200 cells/mm3 that is similar to the 10%–20% reported in the literature from other cohorts.5–8 Patients with CD4 cell counts <200 cells/mm3 had higher overall VACS scores even when the points from CD4 counts were excluded. Although the vast majority of these patients had CD4 counts over 100 cells/mm3, 27% had CD4 counts <100 cells/mm3, which carry high VACS points of 28 or 29 adding to the elevated mortality score in these patients. The VACS index has a C-statistic of 0.76 (0.72–0.80) for 5-year mortality9,10 and the variables in the VACS index, age, CD4 count, HIV RNA, hemoglobin, FIB-4, eGFR, and hepatitis C status, more accurately represent the combined effects of HIV, aging, and multiple physiologic systems on overall mortality risk compared with traditional HIV parameters such as CD4 count and HIV viral load. VACS scores of 20, 50, and 70 indicate an 8%, 25%, and 50% of 5-year mortality, respectively, with an R2-SQ = 0.96.9
Ten percent of patients in our study with CD4 counts <200 cells/mm3 had VACS scores >70, which is associated with an up to a 5-year mortality of 50% as reported in the VACS study.9 The higher scores in patients with CD4 <200 cells/mm3 were driven by significantly higher rates of high-risk indices such as HCV infection, FIB-4 >3.25 (indicating advanced hepatic fibrosis), and anemia, which were significantly more common among patients with CD4 <200 cells/mm3 when compared with those with higher CD4 counts. It is not surprising that patients with lower CD4 counts have higher rates of anemia, which is likely to be multifactorial from marrow suppression and medications. Although there may be an independent effect of HIV-associated inflammation on mortality, variables such as HCV liver disease and anemia that increase inflammation and oxidative stress likely contribute to the higher non-AIDS mortality seen in patients with CD4 counts <200 cells/mm3.
Recently, the application of the VACS index has also been evaluated on short-term mortality. In a study of hospitalized HIV patients, a 5-point increment in VACS index score conferred an approximately 10% increased risk of hospitalization, and given hospitalization, an approximately 10% increased risk of medical intensive care unit admission.11 The index has also been used to evaluate short-term mortality at 1 year after highly active antiretroviral therapy initiation.12 The conclusion drawn from these studies was that the VACS index, representing age and bone marrow, renal, liver and immunologic dysfunction, identifies HIV-infected patients at high risk for hospitalization and poor outcomes. Our study is one of the few looking at the application of the VACS index in clinical populations outside of the VA cohort. The advantage of the VACS index is that all variables can be readily calculated at the clinic visit and may help providers identify areas of the patient's medical history outside of HIV that need to be addressed.
The implications of our findings are that patients with low CD4 counts from a delayed or blunted CD4 recovery after viral suppression have higher morbidity and mortality risk as calculated by VACS scores. As strategies to improve CD4 recovery after viral suppression are being evaluated, treating HCV coinfection and working up and correcting anemia may be beneficial in the short and long term. Elevated Fib-4 is related to HCV coinfection, but other causes of hepatic inflammation such as steatosis from obesity, medications, and alcohol use can increase Fib-4 scores and increase mortality risk and should be addressed. Comorbid conditions such as diabetes, hypertension, and obesity, while not assessed directly in the VACS index, have surrogates such as eGFR and Fib-4 scores that may indicate severity of the condition. With improved treatments for HCV infection, the contribution of HCV to mortality risk including possibly a blunted CD4 reconstitution may be attenuated.
Our study is limited in that we did not include medical and psychosocial comorbidities outside of laboratory parameters. Although these factors impact morbidity and mortality, their assessment was not the objective of our study. The association between VACS score and mortality is beyond the scope of this study and is being evaluated in the VACS and other cohorts.9,10 The strengths of our study include the large sample size and diverse patient population, representative of the current HIV epidemic in the United States.
In conclusion, we found higher rates of high risk VACS variables (>10 points) among patients with suppressed HIV RNA and CD4 counts <200 cells/mm3, and these factors likely contribute to the increased morbidity and mortality reported in these patients. Management of comorbidities such as anemia and HCV liver disease remains important in patients with well-controlled HIV especially among those with blunted CD4 recovery on highly active antiretroviral therapy. The application of the VACS index to the care of HIV-infected patients should be explored to optimize patients' overall health in clinical settings.
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