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J Gen Intern Med. Jul 2002; 17(7): 512–520.
PMCID: PMC1495073

Clinical Importance of HIV and Depressive Symptoms Among Veterans with HIV Infection

Amy M Kilbourne, PhD, MPH,1,2 Amy C Justice, MD, PhD,1,2 Bruce L Rollman, MD, MPH,2 Kathleen A McGinnis, MS,1 Linda Rabeneck, MD, MPH,4 Sharon Weissman, MD,6 Susan Smola, MBA,1 Richard Schultz, PhD,3 Jeff Whittle, MD, MPH,7 and Maria Rodriguez-Barradas, MD5



To compare the clinical importance (association with illness severity and survival) of depressive and HIV symptoms among veterans with HIV infection.


Cross-sectional study; survival analysis.


Infectious Disease Clinics at 3 VA Medical Centers.


HIV-infected patients (N = 881) and their health care providers from June 1999 through July 2000.


Depressive symptoms were assessed using the 10-item Centers for Epidemiologic Studies Depression Scale (CES-D). Patient baseline survey included an HIV Symptom Index measuring the frequency and bother of 20 common symptoms. Providers were surveyed on patients' illness severity, and survival data were obtained from VA death records. Of 881 patients, 46% had significant depressive symptoms (CES-D ≥10). Increasing depression symptom severity was associated with increasing HIV symptom frequency (P < .001) and bother (P < .001). Multiple regression results revealed that having moderate or severe depressive symptoms was not associated with provider-reported illness severity or survival. However, HIV symptoms were significantly associated with provider-reported illness severity (P < .01) and survival (P = .05), after adjusting for moderate and severe depressive symptoms, CD4 cell count/mm3, viral load, age, race, and antiretroviral use.


Depression, while common in this sample, was not associated with illness severity or mortality after adjusting for HIV symptoms. HIV symptoms are associated with severity of illness and survival regardless of patients' severity of depressive symptoms. This suggests that equal medical consideration should be given to HIV symptoms presented by HIV-infected patients regardless of their depression status, rather than automatically attributing medical complaints to depression.

Keywords: HIV/AIDS, symptoms, depression

The clinical importance of coexisting HIV and depressive symptoms remains elusive in the era of highly active antiretroviral therapy (HAART). It is well documented that depressed patients with HIV disease report more somatic symptoms than do nondepressed patients with HIV disease.15 Furthermore, a number of somatic symptoms, including wasting and neurologic symptoms, are associated with poorer health-related quality of life,69 worse functional status,6,7,10 and mortality6,7,11,12 in patients with HIV infection.

Yet clinicians are given little guidance as to what to do in response to symptoms reported by depressed patients with HIV infection. For example, should clinicians first treat the depression and observe whether the somatic symptom (e.g., dizziness, pain) resolves, or should they also search for medical causes of the symptom? The answer may hinge on whether the association between somatic symptoms and outcomes (e.g., disease progression, mortality)1318 is different in patients with co-occurring depressive symptoms. If the association between somatic symptoms and outcomes is as strong in patients with depressive symptoms as in those without depressive symptoms, then providers should consider possible medical causes of the somatic symptoms as well as treat the depressive symptoms.

Thus, determining whether HIV symptoms are clinically significant among HIV-infected patients with co-occurring depressive symptoms is crucial in selecting the best treatment options for the patient. Prior research suggests that providers may not follow up with patients if they assume the symptoms are attributed to a psychiatric condition.19 Yet previous studies examining the role of depression in HIV illness progression and survival did not control for a comprehensive array of symptoms.25,1318 Our study objectives are to determine the clinical importance of HIV and depressive symptoms by determining whether depressive or HIV symptoms are associated with illness severity and 1-year survival among a cohort of HIV-infected patients exposed to HAART.


We used baseline survey data from the Veterans Aging Cohort 3 Site Study (VACS 3), a longitudinal study of HIV-infected veterans from infectious disease clinics at 3 VA Medical Centers in Houston, Cleveland, and Manhattan. Further information on VACS 3 is available elsewhere.20 We collected baseline data from patients and their providers between June 1999 and July 2000. We approached all HIV-infected patients currently attending the infectious disease clinic at 1 of the 3 sites and asked them to self-complete a survey that included questions on depressive and HIV symptoms at the time of their clinic appointment. Patients were paid $10 to complete the survey. We obtained informed consent from all patients participating in this study, and the Human Subjects Committees at all participating sites as well as the University of Pittsburgh institutional review board reviewed and approved VACS 3.

We asked providers to complete a survey regarding their patients' severity of illness and overall disease severity. We collected laboratory data (including CD4 cell count and viral load) using the electronic medical record system with the assistance of the VA Information Resources Management at each site.


Depressive Symptoms

We assessed depressive symptoms in the patient survey using the 10-item version of the Centers for Epidemiologic Studies Depression Scale (CES-D: see Appendix A).21 The CES-D has been widely used in studies of the relationship between HIV and depression.2,3,13,14,22 We used the CES-D 10-item survey rather than a more comprehensive instrument such as the Diagnostic Interview Schedule in order to minimize respondent burden. Patients screened positive for significant depressive symptoms if they obtained a standard cut point of 10 or more out of a possible 30 points. This cut point in the 10-item CES-D has a sensitivity of 96% and specificity of 100% when compared to the CES-D 20-item survey in a sample of older adults in primary care.21 While the CES-D 10-item survey has not been directly compared to clinical diagnoses of major depression, the sensitivity and specificity of the CES-D 20-item survey has been reported to average 80% and 70%, respectively, compared to formal diagnostic interview.23

We also identified veterans who experienced more-severe depressive symptoms by distinguishing those scoring greater than or equal to 15 out of 30 on the CES-D 10-item survey. We derived this cut point from a previously established higher cut point used in the CES-D 20-item survey,24 representing the top 25th percentile of the score distribution. Therefore, we classified those scoring 0 to 9 as having a mild level of depressive symptoms, 10 to 14 as moderate depressive symptoms, and ≥15 representing severe depressive symptoms.

Symptom Frequency and Bother

Veterans completed the HIV Symptom Index to ascertain symptom frequency and bother.25,26 This symptom index measures the frequency and bother of 20 common and bothersome symptoms. The development and validation of the HIV Symptom Index has been described elsewhere by Justice et al.26 The HIV Symptom Index asked whether respondents experienced any one of 20 common symptoms within the past 4 weeks. If they did experience the symptom, patients were asked what the relative level of bother was for each symptom, based on a Likert scale (see Appendix A). Patients who skipped a particular symptom were assumed to not have that symptom. Patients were defined as having a symptom if they reported experiencing it, and were defined as having a “bothersome symptom” if they reported the particular symptom as “it bothers me” or “it bothers me a lot.”

Demographics and Laboratory Data

Patient age and race data were available from the VA administrative files and confirmed by patient and provider report. Antiretroviral (ARV) medication use, including current number of ARV prescriptions at the time of the survey, was obtained from the VA national pharmacy data file. We collected data on CD4 cell count per cubic millimeter (mm3) and viral load (copies per mL) from computerized laboratory records at each site, using lab results collected nearest to the patient survey date.

Outcomes: Severity of Illness and Mortality

For severity of illness, we asked providers how sick their patients were at the time of the visit using a 5-point Likert scale (0 = not sick, 1 = somewhat sick, 2 = moderately sick, 3 = very sick, and 4 = near death), based on a provider clinical judgment question developed and validated by Charlson et al.27 Physician overall assessment of severity of illness using a Likert scale response has been demonstrated to be highly predictive of short-term (in-hospital) and long-term (6-month and 1-year) mortality.28,29

Mortality was ascertained from the Beneficiary Identification and Records Locator Subsystem (BIRLS) Death File, a VA administrative database containing records on all beneficiaries. Fisher et al. (1995) reported a high accuracy rate for BIRLS data in ascertaining mortality.30 Additionally, death information was obtained from administrative inpatient files and from investigators at each VACS 3 site.


We first determined the association between depression and symptom frequency among HIV-infected veterans by comparing the prevalence of each symptom and each bothersome symptom among HIV-infected patients with mild, moderate, and severe depressive symptoms. We then compared the total count of symptoms and bothersome symptoms by adding together the total number of symptoms experienced regardless of bother level, and then adding the total number of bothersome symptoms for each patient.26

Some of the symptoms in the HIV Symptom Index are similar to the depressive symptoms in the CES-D 10-item survey. Previous studies used reduced versions of the CES-D that excluded the somatic symptoms or symptoms that correlated with HIV symptoms.1,13 Therefore, we created an alternative HIV Symptom Index for the bivariate and multivariate analyses that excluded the following symptoms most highly correlated with CES-D score: sadness (r = .68), anxiety (r = .61), sleep problems (r = .56), fatigue (r = .52), and memory loss (r = .48). We also created a reduced CES-D score based on the 5 remaining affective symptoms (feeling bothered, effort, hopeful, happy, and lonely) for the multivariate analysis.

We used multivariate logistic regression analysis to determine whether having moderate or severe depressive symptoms was independently associated with provider-reported severity of illness, controlling for HIV symptom count, in which we modeled the probability of being moderately or very sick, compared to those who were not or somewhat sick.

Cox proportional hazards modeling was used to determine the impact of depressive and HIV symptoms on survival (up to 1 year), using the patients' last visit date as the censor date. Hazard ratios were generated from the Cox model that represent the mortality risk of patients with a given exposure (e.g., significant depressive symptoms) divided by those without the given exposure (no significant depressive symptoms). We assessed the predictive value of the Cox model using the C statistic,31 which is an estimate of the probability that in any pairwise comparison of individuals in the dataset, the individual with the longer predicted survival would actually survive longer.

In both the multivariate logistic and Cox models, we adjusted for CD4 count (<200/mm3 or ≥200/mm3) viral load (<500 or ≥500 copies), age (<50, ≥50 years), race (nonwhite or white), and ARV use (0, 1, 2, 3, 4, 5, or ≥6 ARV prescriptions). For the logistic and Cox regression models, the symptom count variable was normally distributed; hence transformation was not necessary. We also checked for multicollinearity between symptom count, CES-D score, and the other variables using Spearman-Brown correlation coefficients, and all correlations were less than 0.60.

To determine whether the exclusion of overlapping CES-D and HIV symptoms changed our results, we reran the logistic and Cox regression models using both the full and reduced HIV Symptom Index and CES-D score. We also added the interaction between CES-D score (<10, ≥10) and HIV symptom count to determine whether the association between symptoms and severity of illness differed by CES-D score.

We repeated our regression analyses using International Classification of Diseases (ICD)-9 data for depression from the VA computerized medical record system. HIV-infected patients with ICD-9 codes for depression within the past 3 years of the patient survey date were identified using the VA computerized electronic medical record, based on previously established ICD-9 codes from the Veterans Health Study32 and Druss and Rosenheck, 2000.33 ICD-9 codes included depression—single episode (296.2x), depression—recurrent episode (296.3x), depressive disorder (311, 309.10), and neurotic depression (300.4).


Between June 1999 and July 2000, 1,038 HIV-infected patients presented for care at the 3 VA Infectious Disease Clinics; of those, 915 patients were approached. Excluding refusals (N = 34), 881 patients completed surveys, representing 85% of the HIV-infected clinic population at the 3 sites. Of the 881, 99% were male, 55% were African American, 87% were currently taking antiretroviral medications, and the mean age was 49 years (Table 1). Over a quarter (27%) of patients had a CD4 count of less than 200 cells/mm3 and 46% had a viral load of <500 RNA copies. Twenty-two percent were considered at least moderately sick by their health care provider (Table 1).

Table 1
Descriptive Characteristics and Symptom Prevalence

The median CES-D score among the participants was 9 (Table 2). Approximately half (46%) of the sample had moderate depressive symptoms (CES-D score: ≥10), of whom 23% had severe depressive symptoms (CES-D ≥15). Only 57% of patients with severe depressive symptoms were recognized as depressed by their provider. In contrast, almost a quarter (24%) of patients without significant depressive symptoms were considered depressed by their providers. Those with moderate or severe depressive symptoms were more likely to have an ICD-9 code for depression within the past 3 years (P < .001). Overall agreement beyond chance between patient self-reported moderate or severe depressive symptoms and provider report of depression and ICD-9 code was poor (κ = 0.24, κ = 0.25 respectively).

Table 2
Symptoms, Comorbidities, and Severity of Illness in Veterans with HIV/AIDS Cohort Study: Patients by Depression Category (N = 881)

Increasing severity of depressive symptoms was associated with increasing frequency of each HIV symptom (Fig. 1); in all cases, the P value based on the Cochran trend test was <.001. Increasing level of depressive symptoms was also associated with an increasing mean count of HIV symptoms and bothersome HIV symptoms (Table 2; P < .001 based on 1-way ANOVA). After excluding the 5 HIV Symptom Index symptoms most highly correlated with CES-D symptoms, the dose-response association was still evident for increasing level of depression and symptom count and bothersome symptom count (P < .001).

Symptom frequency by depression severity level. In all cases, differences in symptom frequency were significant at P < .001 based on Cochran Test for Trend.

Although median CD4 cell count/mm3 and viral load did not significantly differ between depressive symptom severity levels based on the Wilcoxon nonparametric test (Table 2), both severely and moderately depressed patients were more likely to be considered at least moderately sick than nondepressed patients (P < .001; Table 2).

Regression Results

Univariate regression analyses revealed that an increased HIV symptom count and having severe depressive symptoms (P < .001) were significantly associated with provider-reported illness severity (Table 3). In other words, before adjustment, those with severe depression (CES-D score >15) were twice as likely to be moderately or very sick according to providers (P < .001). HIV symptom count was independently associated with provider-reported severity of illness (P < .01), after adjusting for depressive symptoms, CD4 cell count, viral load, age, race, and antiretroviral use (Table 3). Hence, after adjustment, the odds of being moderately or very sick were 6% higher for each additional symptom. Having moderate or severe depressive symptoms was not independently associated with being moderately or very sick after adjustment.

Table 3
Provider-reported Severity of Illness (Moderately or Very Sick): Logistic Regression Results (N = 780)


After 12 months of follow-up, 53 (7%) of HIV-infected veterans in VACS 3 died. Unadjusted Cox proportional hazards modeling revealed that both HIV symptom count (P < .01) and severe depressive symptoms (P < .05) were associated with mortality (Table 4). After further adjusting for CD4 cell count, viral load, age, race, and antiretroviral use, the association of HIV symptom count with mortality approached significance (P = .05). That is, based on the hazard ratio, the risk of mortality was 3% higher with each additional symptom. There was no association between depressive symptoms and mortality after adjustment. The C statistic of the multivariate Cox model was 0.74, indicating a 74% probability that the HIV-infected patient with the longer predicted survival was in fact the one who survived longer.

Table 4
Time to Death: Cox Proportional Hazards Model Results (N = 780)

The association between HIV symptoms and provider-reported sickness and mortality remained significant even when symptoms overlapping with the CES-D were excluded (data not shown). There was no significant interaction between CES-D score and HIV symptom count (data not shown). In addition, using ICD-9 diagnostic codes for depression in multivariate models instead of CES-D score produced similar results.


Depressive symptoms were common in our sample, with almost a quarter of HIV-infected veterans with severe depressive symptoms. Increasing depression symptom severity was associated with both symptom frequency and higher mean symptom count not only for symptoms considered affective (e. g., anxiety) but also for “physical” (somatic) symptoms.

The high prevalence of depression, and its association with HIV-related symptoms is not surprising, and is consistent with previous studies of medical patients in general34,35 and of HIV-infected patients in care in particular.16,22,36 Previous studies report a depression prevalence of near 50% among HIV-infected patients presenting for care,36,37 similar to what we found.

Yet depressive symptoms among the patients in our sample were not significantly associated with survival after adjusting for HIV symptoms and other factors (CD4 cell count, viral load, age, race, and ARV use). In contrast, HIV symptoms were independently associated with provider-reported severity of illness and survival, whereas depressive symptoms were not associated with these outcomes after adjustment.

To our knowledge, this is the first report to compare the role of depressive and HIV symptoms on mortality using a validated HIV Symptom Index that included a comprehensive array of symptoms. While our results are consistent with other reports that suggest depressive symptoms are not associated with HIV illness progression,1416 other studies suggest the opposite.13,17,18 Prior research in both the pre- and post-HAART era that assessed the impact of depressive symptoms on HIV disease progression and mortality controlled for relatively few HIV-related symptoms. Lyketsos et al. found that depression had no independent effect on AIDS-free survival time and overall mortality among men enrolled in the Multicenter AIDS Cohort Study. HIV symptoms (having “any” versus “none” out of 6 symptoms) were significantly associated with time to AIDS.14 Symptoms measured by Lyketsos et al. (1993) included diarrhea, fatigue, fever, rash, thrush, and weight loss.

In contrast, among a sample of women with HIV infection, Ickovics et al. found an association between depressive symptoms (based on the CES-D excluding somatic symptoms related to HIV) and mortality, controlling for symptom count based on 6 HIV-related symptoms (oral thrush, diarrhea, fever, memory problems, neuropathy, weight changes).13 These differences in findings may be gender related, given that our study and the work by Lyketsos et al. were based primarily on a male population. Hence, potential gender differences regarding the clinical importance of symptoms should be explored in future research.

Our findings suggesting that HIV symptoms are independently associated with severity and survival after controlling for depression are of potential clinical importance. Some have speculated that providers who consider physical symptoms to be depression related may be less willing to follow up and subsequently treat the symptom. In a survey of over 200 providers using patient scenarios, providers were less likely to believe that a patient with a prior psychiatric history who presented a new symptom had a potentially serious physical illness.19 This is perhaps due to the provider's perception that patients with depression exaggerate or somatize their physical symptoms,38,39 although this is not always the case.40 Providers may also express different attitudes toward their depressed compared to nondepressed patients. In one study, patients identified as “difficult” by their providers were more likely to be depressed and more likely to seek care.41 In addition, the poor agreement between patient- and provider-reported depression might potentially be problematic in that providers may assume that clinically significant symptoms are depression related among nondepressed patients. For HIV-infected patients in particular, providers who assume that symptoms are depression related might hesitate to prescribe a more complex antiretroviral regimen, especially if they feel that depression might hinder adherence to the medications.42,43

We recognize the following limitations of this study. The cross-sectional nature of the data brings up the issue of temporal ambiguity by preventing us from determining whether depression leads to greater frequency and bother from symptoms and/or whether the greater frequency and bother from symptoms leads to depression. Distinguishing symptoms that may have psychological or physical origins can be difficult without longitudinal data on symptom progression. Cross-sectional data also prevented us from measuring changes in depressive symptoms, although other researchers have reported that mood tends to remain stable among HIV-infected patients, even with increased HIV illness severity.2,3,16

Second, while we did not find a significant problem with collinearity, such findings comparing the clinical significance of depressive and HIV or other physical symptoms need to be interpreted with caution because of the potential for overlap between depressive and physical symptoms. Although we found no significant interaction between depressive symptoms and HIV symptom count, our power to detect such interactions was low. Because of the cross-sectional nature of the study, further studies are needed to confirm the degree to which depression might have an independent effect on prognosis, given that previous studies are conflicting or inconclusive on this issue.1318

In addition, we employed the CES-D 10-item survey to identify depression, which has limited validity when compared to diagnostic criteria for major depression. While the CES-D 10-item survey was highly correlated with the CES-D 20, formal psychiatric interview remains the gold standard for diagnosing depression, and can better distinguish depressive symptoms attributed to physical or emotional illness. We attempted to mitigate the impact of the measure's low specificity by using 2 different cut points to distinguish patients with more moderate and severe depressive symptoms. We also performed analyses excluding symptoms that overlapped with the HIV Symptom Index, as well as using ICD-9 diagnostic codes to define depression, and similar results were obtained.

We had only 53 deaths for the survival analyses, which limited our power to detect differences in mortality. Our primarily male population that received care at 3 VA sites may limit the generalizability of our findings. Still, VACS 3 includes a large proportion of older, minority, HIV-infected patients, which is expected to become the predominant HIV-infected patient population in the near future.44

In conclusion, our data suggest that HIV symptoms may have the same association with severity of illness and survival regardless of the patient's severity of depressive symptoms. Therefore, if our results are generalizable, providers may want to consider possible physical problems associated with symptoms among patients with depression, and not assume the symptoms are somatic manifestations of depression. Providers may want to give equal consideration to clinical symptoms presented by HIV-infected patients, regardless of their depression status, rather than automatically attributing medical complaints to depression.


The primary funding sources were from a National Institute of Aging (NIA) Career Development Award, a Robert Wood Johnson Faculty Scholar Award, and an Inter-agency Agreement between the NIA, National Institute of Mental Health, and the Department of Veterans Affairs (Dr. Justice, PI). Dr. Rabeneck is the recipient of VA Health Services Research and Development Advanced Research Career Development Award.


Symptom and Depression Measures

The following questions ask about symptoms you might have had during the past 4 weeks. Please circle the one response that best describes how much you have been bothered by each symptom.
I have this symptom and…
HIV Symptom IndexI do not have this symptomIt doesn't bother meIt bothers me a littleIt bothers meIt bothers me a lot
a. Fatigue or loss of energy?*12345
b. Fevers, chills, or sweats?12345
c. Feeling dizzy or lightheaded?12345
d. Pain, numbness, or tingling in the hands or feet?12345
e. Trouble remembering?*12345
f. Nausea or vomiting?12345
g. Diarrhea or loose bowel movements?12345
h. Felt sad, down, or depressed?*12345
i. Felt nervous or anxious?*12345
j. Difficulty falling or staying asleep*12345
k. Skin problems, such as rash, drying, or itching?12345
l. Cough or trouble catching your breath?12345
m. Headache?12345
n. Loss of appetite or change in the taste of food?12345
o. Bloating, pain, or gas in your stomach?12345
p. Muscle aches or joint pain?12345
q. Problems with having sex, such as loss of interest or lack of satisfaction?12345
r. Changes in the way your body looks, such as fat deposits or weight gain?12345
s. Problems with weight loss or wasting?12345
t. Hair loss or changes in the way your hair looks?12345
CES-D 10-item Survey
For each of these statements, please indicate how often you felt this way during the past week.
During the past week…Rarely (<1 day)Some/little (1–2 days)Much (3–4 days)Most (5–7 days)
a. I was bothered by things that usually don't bother me1234
b. I had trouble keeping my mind on what I was doing*1234
c. I felt that everything I did was an effort1234
d. I felt depressed*1234
e. I felt hopeful about the future1234
f. I felt fearful*1234
g. My sleep was restless*1234
h. I was happy1234
i. I felt lonely1234
j. I could not get “going”*1234
*These symptoms were excluded to create CES-D 5 and HIV symptom 15-item index.


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