HIV disease progression: depression, stress, and possible mechanisms

HIV Disease Progression: Depression, Stress, and Possible Mechanisms Jane Leserman There is much interest in whether depression and stress may explain the wide variability in the disease course of patients infected with human immunodeficiency virus (HIV). This article summarizes the large body of evidence examining whether depression and stress may have an impact on immune- and disease-related parameters in HIV disease. Furthermore, we review what is known about the underlying biological mechanisms of HIV disease, such as alterations in glucocorticoids and catecholamines, which may help explain these psychoimmune relationships. Our review of the literature finds substantial evidence that chronic depression and stressful events may affect HIV disease progression. We know little, however, regarding the biological mechanisms that may account for these relationships. More research is warranted to investigate how depression and stress might impact HIV disease progression and what types of interventions might mitigate the negative impact of chronic depression and trauma. Biol Psychiatry 2003;54:295–306 © 2003 Society of Biological Psychiatry Key Words: Human immunodeficiency virus, acquired immunodeficiency syndrome, depression, stress, psychoneuroimmunology, cortisol, sympathetic nervous system

infection. First, HIV is a multifactorial disease, affecting biological systems that overlap those affected by depression and stress. There is a large body of literature pointing to the harmful effects of stress and depression on cellular immunity, including those aspects of the immune system affected by HIV (Evans et al 1989; Herbert et al 1993a, 1993b; Stein et al 1991; Weisse 1992). Second, depression and stress have been associated with a worsening course of other diseases that affect the immune system. For example, among cancer patients, severe life stress has been associated with a greater probability of relapse (Ramirez et al 1989), and psychosocial interventions to improve coping with stress have resulted in longer survival (Fawzy et al 1993; Spiegel et al 1989). This article reviews research examining how depression and stressful life events affect morbidity and mortality in HIV infection. We will also review what is known about the underlying biological mechanisms (e.g., alterations in the hypothalamic–pituitary–adrenal [HPA] axis and sympathetic nervous system [SNS]) that may help explain these psychoimmune relationships. Understanding the psychological, endocrine, and SNS effects on HIV disease may aid in the development of interventions for this chronic illness.

Introduction

Depression and HIV Disease Progression

D

Progression of HIV infection occurs slowly, and therefore studies done over short periods tend to have little change to explain. Thus, it is not surprising that short-term studies have not shown a relationship between depression and HIV disease markers (Eich-Hochli et al 1997; Perry et al 1992; Rabkin et al 1991; Vedhara et al 1999). The best evidence for a relationship between depression and HIV disease progression comes from longitudinal studies conducted over long periods (see Table 1). The San Francisco Men’s Health Study, a 9-year longitudinal study of 395 gay HIV-infected and initially asymptomatic men, found faster progression to AIDS among those classified as depressed at study entry (PageShafer et al 1996), based on the Center for Epidemiologic Studies Depression Scale (CES-D) (Radloff 1977). Median time to first AIDS diagnosis was 6.2 years for those

espite recent advances in the treatment of human immunodeficiency virus (HIV) infection (e.g., protease inhibitors), there remains great variability in the course of this disease, including variable length of time before an AIDS diagnosis and mortality. Early in the HIV epidemic, researchers began focusing on the effects of depression and stress as possible mechanisms relating to variations in HIV disease progression. There are a number of reasons why a psychoneuroimmunologic approach might help explain variability in the course of HIV

From the Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina. Address reprint requests to Jane Leserman, University of North Carolina at Chapel Hill, Department of Psychiatry, CB7160, Chapel Hill, NC 27599-7160. Received November 4, 2002; revised January 27, 2003; accepted March 10, 2003.

© 2003 Society of Biological Psychiatry

0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00323-8

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Table 1. Summary of Longitudinal Studies Examining Depression and HIV Disease Progression HIV-infected Population

Follow-up Years

Burack et al 1993a

277 gay men

5.5

Baseline CES-D

Page-Shafer et al 1996a

395 gay men

9

Baseline CES-D

Mayne et al 1996a

402 gay men

7

Time-varying CES-D

Lyketsos et al 1993b

1339 gay men

8

Baseline CES-D

Lyketsos et al 1996bb

911 gay men

10

Leserman et al 1997c

66 gay men

2

HDRS modified to exclude HIV-type symptoms

Leserman et al 1999c

82 gay men

5.5

Leserman et al 2000c

82 gay men

7.5

Study

Measure of Depression

CES-D

Leserman et al 2002c

82–96 gay men

9

Patterson et al 1996

414 gay men

5

Time-varying HDRS modified to exclude HIV-type symptoms Time-varying HDRS modified to exclude HIV-type symptoms Time-varying HDRS modified to exclude HIV-type symptoms Baseline HDRS

Ickovics et al 2001

765 women

7

CES-D

Findings Depressed had more rapid decline in CD4 count; depression not related to AIDS or mortality Depressed had 1.4 years faster progression to AIDS; depression did not predict mortality in multivariate model Men with elevated depression at each visit had 1.67 greater risk for mortality compared with men who never had elevated depression Depression not related to change in CD4 count, AIDS, or mortality During the 6 –18 months before diagnosis with AIDS, there is a dramatic rise in depression Depressive symptoms during the preceding 2 years were related to greater decline in CD8⫹ T cells, and CD56⫹ and CD16⫹ NK cells; depression effects were more pronounced among those with more stressful events. The risk of AIDS was doubled for every cumulative average increase of one severe depressive symptom Trend for depressive symptoms to be related to AIDS progression (p ⫽ .06) when other psychosocial variables were not in the model Depressive symptoms were not related to AIDS progression but were predictive of faster development of an AIDS indicator or clinical condition Depressive symptoms associated with faster mortality but not to change in CD4 count or AIDS Chronic depressive symptoms (CES-D elevated at 75% or more of visits) associated with two times the risk of death and greater decline in CD4 count compared with limited or no depressive symptoms (CES-D elevated 0% to 25% of visits)

HIV, human immunodeficiency virus; CES-D, Center for Epidemiologic Studies Depression Scale; HDRS, Hamilton Depression Rating Scale; AIDS, acquired immunodeficiency syndrome. a San Francisco Men’s Health Study b Multicenter AIDS Cohort Study c Coping in Health and Illness Study

who were depressed at baseline compared with 7.6 years for those who were not depressed. Findings held when controlling for baseline measures of demographic variables, CD4 T lymphocyte count, HIV-related medical symptoms, and health habits. These findings at 9 years from the San Francisco Men’s Health Study were at odds

with earlier data from the same cohort at 5 years showing no relationship between baseline depression and progression to AIDS (Burack et al 1993). The earlier study, however, showed an association between baseline depression and decline in CD4⫹ T lymphocytes. In a Cox regression analysis of the same cohort at 7 years of

HIV: Depression, Stress, and Mechanisms

follow-up, researchers found that those who had elevated symptoms of depression at every visit, had a 1.7 times greater risk of mortality compared with those who never had an elevated depression score (Mayne et al 1996). In another study, involving 414 HIV-infected gay men studied over five years, baseline depression was associated with shorter time to death but not significantly associated with change in CD4⫹ count or progression to AIDS (Patterson et al 1996). An analysis of 1809 gay men from the Multicenter AIDS Cohort Study found no relationship between depression measured with the CES-D at study entry and progression of HIV infection during 8 years of follow-up (Lyketsos et al 1993). Disease progression was defined as time to AIDS, death, or decline in CD4⫹ T lymphocytes. In later analyses of these data, the authors found that self-reported depressive symptoms appeared to rise during the 1.5 years before an AIDS diagnosis (Lyketsos et al 1996b). The authors interpret these findings as an indication that depression may increase toward the later stages of HIV infection and thus may be a manifestation of the disease process. A subsequent survival analysis of these data, however, using level of depressive symptoms during the 6 months before an AIDS diagnosis, showed no relationship between depression and time to death (Lyketsos et al 1996a). The relationship between depression and HIV disease progression appears somewhat clouded by the timing of the depression measurement relative to disease change. Two limitations of the longitudinal studies reported above include the focus on measuring depression at study entry and ignoring continuous data on depressive symptoms, thereby limiting variance on this measure. It would seem unlikely that a one-time measure of depression would predict disease progression as many as 9 years later. A more robust test of the hypothesis that depressive symptoms may affect HIV disease progression might be to examine depressive symptoms as a time-dependent variable in Cox regression. Such an analysis lets the value of depressive symptoms (a continuous score) change at each time point, so that the cumulative effects of depression during periods before change in disease status can be examined. For example, scores on depressive symptoms at visit three are based on the cumulative average of visits one and two; likewise, scores on depressive symptoms at visit five are based on the cumulative average of visits one through four. Leserman and colleagues presented such an analysis from the Coping in Health and Illness Project (CHIP), a study of 96 initially asymptomatic HIV-infected gay men followed-up every 6 months, using data at 5.5 years (Leserman et al 1999) and 9 years (Leserman et al 2002). Increased risk of AIDS was associated with higher cumulative depressive symptoms at 5.5 years of follow-up, as

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Figure 1. Kaplan-Meier estimate of the distribution of time (in months) until an AIDS clinical condition by depressive symptoms.

measured by a modified Hamilton Depression Rating Scale (Hamilton 1960) (excluding somatic symptoms that could be related to HIV disease change). For every cumulative average increase of one severe depressive symptom (3-point increase on the Hamilton Depression Rating Scale), the risk of AIDS doubled. An earlier analysis of the CHIP cohort showed that depressive symptoms, especially in the presence of severe stress, were related to declines in several lymphocyte subsets (e.g., CD16⫹ and CD56⫹ natural killer [NK] cells, and CD8⫹ cytotoxic-suppressor cells) over a 2-year period (Leserman et al 1997). There is some evidence that NK cells might have a role in suppressing HIV and thus have clinical significance. For example, low NK cell responsiveness to interferon ␣ has been linked to higher risk of death (Ullum et al 1999); NK cells have been shown to lyse HIV-infected cells in vitro (Bandyopadhyay et al 1990); NK cells isolated from HIV-infected subjects have suppressed HIV entry and replication (Oliva et al 1998); and NK cells have been negatively related to HIV viral load (Ironson et al 2001). CD8⫹ T lymphocytes may inhibit HIV replication early in the infection (Barker 1999; Famularo et al 1997; Price et al 1999). More recently, the CHIP team reported that men with more cumulative depressive symptoms had increased risk of developing an AIDS clinical condition by 9 years of follow-up (Leserman et al 2002). For each 3-point change in average depressive symptoms (equal to one severe symptom), the risk of developing a clinical AIDS condition was more than doubled. Figure 1 shows the KaplanMeier survival curves for continuing without an AIDS clinical condition for those above and below the median on depressive symptoms. Note that these curves are only approximations, because they do not include control variables. The trajectory to an AIDS condition is approxi-

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Table 2. Cox Regression Model: Risk of Depression with HIV Disease, Psychosocial, and Control Variables

Baseline Variable Major depression before study entry Time-dependent Lagged Variables Presence of AIDS clinical condition Social conflict

␤

p

Risk Ratio

95% CI

1.56

.0001

4.77

2.17, 10.47

.74 .93

.10 .0005

2.09 2.54

.86, 5.07 1.50, 4.31

Table shows the results of a stepwise Cox regression allowing variables with p ⬍ .15 to stay in the model. Variables not making it into the model include age, race, education, number of anti-retroviral medications used, and CD4 cell count. HIV, human immunodeficiency virus; CI, confidence interval; AIDS, acquired immunodeficiency syndrome.

mately twice as fast among those above the median in depressive symptoms compared with those below the median. At 9 years of follow-up, 29% of the CHIP study patients had developed a major depression at least once. Note that the 9-year analysis did not replicate earlier findings of a relationship between depressive symptoms and progression to AIDS (based on drop in CD4 to less than 200 and/or an AIDS clinical condition) (Leserman et al 1999). At 7.5 years, there was a trend for depressive symptoms to predict progression to AIDS (Leserman et al 2000). Also examining the effects of chronic depression, Ickovics et al (2001) recently reported mortality findings in a 7-year study of 765 HIV-infected women. These investigators found that women with chronic depressive symptoms (e.g., CES-D scores ⱖ 16 for at least 75% of visits) were about two times more likely to die from HIV than were women never experiencing depression. Mortality for those with intermittent depression was 1.6 times greater than for those without depression. These findings controlled for baseline CD4⫹ cell count, HIV ribonucleic acid (RNA) viral load, HIV-related symptoms, antiretroviral medication use, age, and employment status. The effects of depression on mortality were more pronounced among those who began the study with lower CD4⫹ counts and thus were at greater risk of death. Chronic depression was also associated with a greater decrease in CD4⫹ cell counts over time. In a cross-sectional analysis of HIVinfected women, Evans et al (2002) found that depression and anxiety symptoms were correlated with lower NK cell activity, higher HIV RNA viral load, and higher activated CD8⫹ T lymphocytes. Activated CD8 cells (CD8⫹/ CD38⫹/DR⫹) have been correlated with cytotoxic activity and HIV disease progression (Giorgi et al 1999; Ho et al 1993; Liu et al 1998). To summarize, a more robust relationship between depression and HIV disease progression is found in studies performed over long periods and in those analyzing the chronic effects of depression (e.g., as a time-dependent variable in Cox regression or as multiple time points with elevated depression scores). Despite this association, we must still examine whether depression puts HIV-infected

persons at greater risk for disease progression or whether changes in disease might be associated with increased risk of depression.

Depression and HIV Disease Progression: Causal Relationship? Studies have tried to address the “chicken-or-the-egg” issue of whether depression is a predictor or result of disease progression by measuring depression in the intervals before AIDS or the development of medical symptoms. This approach helps establish whether the depressive symptoms occurred before changes in disease status. If disease changes are gradual, however, this approach may not address the order of events. In attempting to address the causal nature of the depression– disease progression relationship, we have reexamined the 9-year longitudinal data from the CHIP study (of 96 HIV-infected men). We used a stepwise Cox regression model (with EXACT method for handling ties and p ⬍ .15 for remaining in the model) to examine the effects of psychosocial and HIV disease–related variables on the development of major depression (assessed with the Structured Clinical Interview for DSM-III-R Disorders [Spitzer et al 1990] and diagnoses based on consensus diagnostic conferences [Perkins et al 1994]). The predictor variables included: 1) major depression before entering the study; 2) CD4⫹ cell count (methodology described previously [Leserman et al 2002]); 3) AIDS clinical condition (Centers for Disease Control stage “C” [Anonymous 1992]); 4) conflict in social relationships (O’Brien et al 1993; Leserman et al 1994); and 5) control variables (age, education, race, number of antiretroviral medications). The variables of CD4⫹ cell count, AIDS clinical condition, social conflict, and antiretroviral medications were measured every 6 months, were treated as time-varying measures, and were lagged 6 months before the measurement of depression. The final stepwise model predicting major depression is shown in Table 2. Note that those who had a major depression before the study had almost a fivefold increased risk of depression during the 9 years of the study. Stated another way, 61% of those who devel-

HIV: Depression, Stress, and Mechanisms

oped a major depression during the study had been depressed at least once before baseline. Those with more social conflict (e.g., argued and irritated with people, frequent unpleasant social interactions) also had increased risk of depression (e.g., for each 1-unit increase on the 5-point conflict scale, the risk of depression more than doubled). CD4⫹ cell count and developing an AIDS clinical symptom did not predict major depression; however, as reported above, depressive symptoms did predict increased risk of developing AIDS (Leserman et al 1999) and an AIDS clinical condition (Leserman et al 2002). Thus, it appears that depression may be more likely to lead to clinical disease change than vice versa. Developing depression in HIV may be more a function of having been depressed previously and having conflicting social relationships.

Stress and HIV Disease Progression Another approach to determining whether psychological factors may impact on HIV disease progression has been to examine the impact of stressful events, such as bereavement and other types of trauma, on changes in disease status (see Table 3). The stress of bereavement, for instance, has been shown to correlate highly with subsequent development of depression (Bruce 2002). The advantage of studying persons experiencing stress or trauma is that the direction of the relationship between stressful events and HIV disease change may be somewhat less ambiguous than the effects of depression on disease course, depending on the nature of the stressor studied.

Bereavement Given that HIV-infected persons are at high risk for having a partner or close friend die, many studies have examined the stress of bereavement in HIV-infected persons. Kemeny and Dean (1995) showed that bereavement before study entry (having a close friend or lover who died of AIDS) was associated with more rapid decline in CD4⫹ count over 3– 4 years. These findings among 85 gay men were not explained by differences in health habits, antiretroviral medication use, or age. Bereavement did not predict progression to AIDS or mortality. A later study among bereaved men reported that those who found meaning in bereavement showed less rapid decline in CD4⫹ levels and lower rates of mortality due to AIDS during 2–3 years of follow-up (Bower et al 1998). In analyzing a subsample from the Multicenter AIDS Cohort Study study, Kemeny et al (1995) found that recently bereaved men had increases in serum neopterin (an im-

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mune activation marker associated with increased risk of AIDS) and decreases in lymphocyte proliferative response to phytohemagglutinin compared with a matched group of non-bereaved subjects (Kemeny et al 1995). In a 6-month study, Goodkin et al (1996) showed that bereaved HIVinfected men had decreased lymphocyte proliferative response to phytohemagglutinin and decreased natural killer cell cytotoxicity compared with non-bereaved subjects (Goodkin et al 1996). In later studies, Goodkin et al (1998, 2001) reported that a 10-week bereavement support group intervention was associated with higher CD4 counts, larger decreases in HIV RNA viral load, greater numbers of total T lymphocytes, decreases in plasma cortisol, and fewer health care visits, compared with a standard-care control condition. Thus, bereavement appears to have a negative effect on the immune response of those infected with HIV, a response that may be altered by treatment for the bereaved.

Other Trauma and Stressful Life Events In addition to bereavement, researchers have focused on the negative health impact of other types of trauma and a wide variety of stressful life events. Ironson et al (1994) found that men with greater distress at the time of HIV serostatus notification had a greater chance of developing HIV-related clinical symptoms at 2-year follow-up. A recent study among 67 asymptomatic HIV-infected African American women found that 62% of the sample had experienced a traumatic event during their lifetime (e.g., death of child, assault, rape) (Kimerling et al 1999). Traumatic exposure, particularly among those with posttraumatic stress disorder, was associated with greater decrease in the CD4⫹/CD8⫹ ratio at 1-year follow-up. In a study of 618 HIV-infected children and adolescents (ages 1–20 years), having two or more stressful life events (e.g., family member death, major illness or loss) was associated with almost a threefold increased risk of immune suppression (decline in CD4⫹ percent) at 1-year follow-up (Howland et al 2000). Patterson et al (1995) showed that HIV-infected gay men with less severe life adversity in combination with less depression were at lower risk for negative alterations in their immune status (e.g., CD4⫹ percent) at 6-month follow-up (Patterson et al 1995). Other studies using short follow-up periods and/or questionnaire methods to assess life stress have generally not shown an association between stress and reduction in CD4⫹ T lymphocyte counts (Kessler et al 1991; Perry et al 1992; Rabkin et al 1991). Research on the adverse health effects of stressful life events in HIV infection has been most consistently reported by the CHIP study during 9 years following the same cohort of gay men (Evans et al 1995; Leserman et al

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Table 3. Summary of Longitudinal Studies Examining Stress and HIV Disease Progression Study

HIV-infected Population

Follow-up Time

Measure of Stress

Kemeny and Dean 1995

85 gay men

3– 4 years

AIDS-related bereavement

Goodkin et al 1996

79 gay men

6 months

AIDS-related bereavement

Ironson et al 1994

23 gay men

2 years

HIV serostatus notification

Kimerling et al 1999

67 African American women

1 year

Traumatic events

1 year

Major negative life events

6 months

Interview-based rating of events and difficulties Self-report rating of stress using PERI

Howland et al 2000

618 children and adolescents

Patterson et al 1995

63 gay men

Patterson et al 1996

414 gay men

5 years

Leserman et al 1997a

66 gay men

2 years

Interview-based rating of events and difficulties from PERI

Evans et al 1997a

93 gay men

3.5 years

Leserman et al 1999a

82 gay men

5.5 years

Leserman et al 2000a

82 gay men

7.5 years

Leserman et al 2002a

82–96 gay men

9 years

Interview-based rating of events and difficulties from PERI Interview-based rating of events and difficulties from PERI Interview-based rating of events and difficulties from PERI Interview-based rating of events and difficulties from PERI

Capitanio et al 1998

18 male rhesus macaques with simian immunodeficiency virus

2-year experiment

Unstable social condition to induce stressful state

Findings Men who experienced bereavement before study entry had more rapid loss of CD4 T-cells Bereaved had lower NK cell cytoxicity and lymphocyte proliferative response to PHA Men with more distress at serostatus notification were at greater risk for HIV-related clinical symptoms Women with past trauma, especially with PTSD, had greater decreases in CD4/ CD8 ratio Two or more stressful life events were associated with almost a three fold increased risk of CD4⫹ percent decline Men without stressful events or depression had less risk of decline in CD4⫹ percent Negative life events were not associated with advance in symptoms, CD4⫹ cell count, AIDS, or mortality Severe stress was related to greater decline in CD8⫹ T cells and CD16⫹ NK cells: stress effects were more pronounced among those with more depressive symptoms The risk of HIV disease stage progression was doubled with every increase in one severe stressor per 6-month interval The risk of AIDS was doubled for every cumulative average increase of one severe stressor The risk of AIDS was doubled for every cumulative average increase of one severe stressor The risk of AIDS was increased by 75% and the risk of a clinical AIDS condition was tripled for every cumulative average increase of one severe stressor Animals exposed to the unstable social condition had shorter survival and lower plasma cortisol levels than those in the stable condition

HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; PHA, phytohemagglutinin; PTSD, posttraumatic stress disorder; PERI, Psychiatric Epidemiology Research Interview. a Coping in Health and Illness Study

1997, 1999, 2000, 2002; Petitto et al 2000). The CHIP stressful life events and difficulty measure, assessing 111 stresses, is based on interviewer contextual ratings that exclude stresses that could have resulted from disease progression (e.g., retirement due to HIV worsening). By using interviewer-based contextual ratings rather than

questionnaires with patient’s stress ratings, this measure attempts to reduce the possibility that worsening disease could have led to poor coping and thus higher stress scores. In addition, interview-based approaches to measuring stress may be more accurate than questionnaires, in that they avoid counting the same stress more than once,

HIV: Depression, Stress, and Mechanisms

and the variability within a stress category is not ignored because the context of the stress is considered. At CHIP study baseline, men with more severe stressful life events in the preceding 6 months were shown to have lower NK cell counts (CD16⫹ and CD56⫹) and fewer cytotoxic/suppressor cells (CD8⫹ T lymphocytes) compared with those with less stress (Evans et al 1995). In the same cohort, prior severe stress and depressive symptoms were independently associated with decreases in NK cell counts and CD8⫹ T lymphocytes after 2 years (Leserman et al 1997). Subjects who scored above the median on both stress and depressive symptoms were most likely to have decreases on these immune measures (e.g., one half to two thirds of an SD drop on immune measures from baseline). As noted above, decrements in these lymphocyte subsets may have clinical significance in HIV (Bandyopadhyay et al 1990; Barker 1999; Famularo et al 1997; Ullum et al 1999; Ironson et al 2001; Oliva et al 1998; Price et al 1999). The CHIP investigators have also directly investigated the role of stressful life events on the clinical outcome of gay men infected with HIV. Among men studied up to 3.5 years, Evans et al (1997) reported that severe stress was associated with greater risk for worsening HIV disease stage (e.g., drop in CD4⫹ or development of HIV clinical symptoms). For every one severe stress per 6-month study interval, the risk of early disease stage change was doubled. At 5.5 (Leserman et al 1999), 7.5 (Leserman et al 2000), and 9 years (Leserman et al 2002) of follow-up of CHIP patients, Leserman and colleagues reported that higher average cumulative stressful events were predictive of faster progression to AIDS (decline in CD4⫹ T lymphocytes to less than 200 and/or AIDS indicator condition). At these three time points, the study showed that for every increase in cumulative average stress equivalent to one severe stressor or two moderate stressors, the risk of AIDS was approximately doubled. Note that only those subjects who began the study without AIDS were included in these analyses (n ⫽ 82). The AIDS progression rate at the end of 8 years for those above the median in stress during the 9 years was 74%, compared with 40% for those below the median. Leserman et al (2002) also reported that for every increase in cumulative average stress equivalent to one severe stressor, the risk of developing an AIDS clinical condition (e.g., Kaposi sarcoma, Pneumocystis pneumonia) was approximately tripled (Leserman et al 2002). Limitations of the CHIP study include problems in generalizing from a relatively small, nonrepresentative sample of gay men from North Carolina; most subjects progressing before widespread use of highly active antiretroviral therapy (HAART); and lack of control for length of time with HIV infection. Analyses did include controls

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for demographic variables, baseline CD4⫹ T cell count, baseline HIV RNA viral load, number of antiretroviral medications, and serum cortisol. Furthermore, measurement of cumulative average stress was lagged by 6 months before HIV disease progression, with removal of stressors related to HIV disease changes. Interviewer-based stress ratings lessen the possibility that worsening disease could have led to poor coping and thus higher stress scores. The association in the CHIP study of stressful events with multiple measures of disease progression (e.g., AIDS, clinical AIDS condition, change in HIV disease stage, and T lymphocyte subset decline) lends convergent validity to these stress–immune– disease progression findings.

Experimental Stress Capitanio et al (1998) examined the effects of an experimentally manipulated social stress (e.g., unstable social group) on survival of male rhesus macaques infected with simian immunodeficiency virus (SIV). The unstable group animals (high stress) had significantly shorter survival (169 days) compared with those in the stable group (low stress). Animals that received threats from other animals had higher SIV RNA levels (viral load) than did those not receiving threats, regardless of social condition. Animals who engaged in grooming (less stressed) had lower SIV RNA levels. Thus, studies in humans and rhesus macaques indicate that stressful events and trauma may have a negative impact on HIV (SIV) disease progression. More consistent findings are associated with studying subjects over longer periods and examining actual stressors (e.g., bereavement) or using contextually based interviews rather than questionnaire assessments of stress.

Potential Mediating Mechanisms Thus far, we have presented evidence that depression and stress may be predictive of HIV disease progression. The mechanisms mediating these relationships are less clear. Although it is possible that poor health habits (e.g., smoking, substance abuse, risky sexual behavior, medication use) related to stress and depression might account for these findings, studies have not found that such health habits diminish the psychoimmune relationships (Goodkin et al 1996; Ickovics et al 2001; Kemeny and Dean 1995; Kemeny et al 1995; Leserman et al 2000, 2002; PageShafer et al 1996). We need studies examining the possible mediating role of HIV medication adherence. In terms of biological mediators, most HIV literature to date has focused on the HPA axis and SNS as possible mediators, based on animal and human research linking

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immune status changes to dysregulation in these biological systems (Cupps et al 2002; Friedman et al 1997). For these systems to be involved in mediating the psychoimmune relationships in HIV, we must establish that hormones of the HPA axis and SNS are affected by stress and depression and that dysregulation of these systems in turn may have negative immunologic and disease progression consequences in HIV infection.

Neuroendocrine Pathway Because disturbances of HPA axis function (e.g., increases in adrenocorticotrophin-releasing hormone and cortisol) have been associated with stress and depression in humans, and such dysregulation may negatively impact the immune response, we will examine the evidence that glucocorticoids may be a mediating mechanism explaining the negative immune effects of depression and stress in HIV infection. There is some research showing that cortisol is positively related to stress and depression in HIV. In HIV-infected men, Gorman et al (1991) found that urinary cortisol was higher in those who were depressed and anxious, and Goodkin et al (1996) found higher cortisol levels in the bereaved versus non-bereaved. Those HIV-infected men who were in a cognitive behavioral intervention had less increase in cortisol/dehydroepiandrosterone (DHEA) ratio compared with a wait-list group (Cruess et al 1999). Furthermore, among those given cognitive behavioral therapy, decreases in perceived stress and anxiety have been associated with declines in cortisol and the cortisol/DHEA ratio (Cruess et al 1999; Cruess DG et al 2000; Cruess S et al 2000). Serum cortisol was not related to stress or depression during 7.5 and 9 years of follow-up in the CHIP study (Leserman et al 2000, 2002), and urinary cortisol was only associated with depressed and anxious mood at one assessment in another 2-year study (Kertzner et al 1993). Discrepant findings may be due to the time when cortisol was measured, the use of serum versus an integrated 24-hour urinary measure, the stage of HIV-infected persons studied, and the focus on chronic versus acute stress. There are several pathways by which cortisol could affect changes in immune function and HIV disease progression. Cortisol may stimulate HIV viral replication (Corley 1996), modify programmed cell death, and alter the pattern of cytokines secreted (from Th-1 to Th-2) (Clerici et al 1997; Corley 1996; Daynes et al 1991, 1995), changes that have been associated with HIV disease progression (Clerici et al 1997; Maggi et al 1994). Clerici et al (1997) have suggested that increases in glucocorticoids and decreases in DHEA during HIV infection may alter the pattern of cytokines secreted by suppressing

J. Leserman

beneficial Th-1 cytokines (e.g., interleukin [IL]-2, interferon ␥) in favor of Th-2 cytokines (e.g., IL-4, IL-6, IL-10). Reductions in the Th-1 cytokines have been linked to HIV progression (Clerici et al 1997; Vago et al 1994), although the nature of these relationships in HIV remains controversial (Graziosi et al 1994; Maggi et al 1994). An early study showed greatly increased HIV replication when hydrocortisone was added to the cell cultures of AIDS patients (Markham et al 1986). In another in vitro study, Nair et al (1995) found inhibition of NK cell activity when cortisol or adrenocorticotrophin-releasing hormone was added to cell cultures of AIDS patients. Glucocorticoids may affect HIV pathogenesis directly, through increased viral replication, or more indirectly by inhibiting the immune response to other pathogens. Summarizing the results of five retrospective and prospective clinical studies, Christeff et al (1997) found that CD4 cell counts were negatively associated with serum cortisol and positively related to serum DHEA. Furthermore, cortisol levels were significantly greater in HIVpositive than in HIV-negative men, especially during later stages of HIV infection (Christeff et al 1997). Goodkin et al (1998) showed that increased CD4⫹ cell counts were associated with reductions in cortisol after a bereavement support group. Under conditions of stress, cortisol has been associated with decreases in mitogen response and lower lymphocyte functioning in HIV (Antoni et al 1991; Goodkin et al 1996). At baseline, the CHIP study found that the effects of stress on killer lymphocytes were amplified in those with high levels of cortisol (Petitto et al 2000). Although at 7.5 and 9 years this study did not show that cortisol mediated the effects of stress on progression to AIDS, increases in cortisol were clearly related to three markers of disease progression (AIDS, clinical AIDS condition, and mortality) (Leserman et al 2000, 2002). For every 3 ␮g/dL increase in cumulative average serum cortisol, there was a 40% increased risk of AIDS, and approximately a 2.5-fold increased risk of developing an AIDS clinical symptom or dying from HIV infection (Leserman et al 2002). Increased plasma cortisol has also been linked to a social stressor in rhesus macaques and with accelerated SIV disease progression (Capitanio et al 1998). Other clinical studies, however, have not shown a relationship between CD4⫹ T lymphocytes and cortisol (Kertzner et al 1993; Gorman et al 1991). Although there are some conflicting reports regarding the neuroimmunomodulatory effects of glucocorticoids, the majority of studies do show a relationship between cortisol and HIV disease markers. The causal direction of this relationship, however, remains controversial, and more research is needed to clarify whether glucocorticoids have a mediating role in explaining the effects of stress and depression on disease progression in HIV.

HIV: Depression, Stress, and Mechanisms

Sympathetic Nervous System Pathway Chronic elevations of SNS activity (e.g., norepinephrine [NE]) among those infected with HIV may adversely affect immune system functioning (e.g., reduced lymphocyte proliferation, alteration in cytokine production). It has been suggested that NE may suppress Th-1 type cytokines and increase Th-2 type changes associated with increased risk of HIV viral replication and increased vulnerability to opportunistic infections (Clerici et al 1997; Cole and Kemeny 1997; Cole et al 1998; Vago et al 1994). Cole et al (2001) have shown that HIV-infected gay men with higher baseline levels of autonomic nervous system (ANS) activity (e.g., systolic blood pressure, skin conductance, electrocardiogram interbeat interval) had poorer suppression of plasma RNA viral load and worse CD4⫹ T cell recovery after receiving HAART compared with men with lower levels of ANS activity. In vitro studies by the same team have shown that NE can enhance HIV viral replication and viral gene expression (Cole et al 1998, 2001). Moreover, HIV-infected men who had greater declines in NE after a cognitive behavioral intervention had higher T-cytotoxic/suppressor lymphocytes compared with those with higher NE (Antoni et al 2000). Circulating catecholamines have also been shown to increase in response to psychological stress (Dimsdale and Ziegler 1991; Ward et al 1983), and depression has long been associated with various alterations in the noradrenergic system. Although difficult to assess in humans, such alterations may include changes in sympathetic pathways that innervate immune organs, such as the spleen (Anand et al 2000; Friedman et al 1997). Irwin et al (1990) have used an animal model that may be relevant to processes involved in depression and anxiety syndromes in humans. They have shown that increased emotional reactivity after intracerebroventricular corticotropin-releasing factor administration activates descending sympathetic pathways that induce marked reductions in the function of NK lymphocytes residing in the spleen. Although there is less HIV research on the immune effects of the SNS compared with the HPA axis, dysregulation in the SNS in response to stress and depression might be another significant mediating mechanism underlying the effects of stress and depression on HIV disease progression.

Substance P Although the HPA axis and the SNS have been the most studied pathways mediating psychological effects on HIV disease progression, neuropeptide substance P has also been implicated. A substance P antagonist has been efficacious for the treatment of depression (Hokfelt et al 2001), and substance P may be involved in the modulation

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of HIV infection (Douglas et al 2001; Ho et al 1996). Plasma levels of substance P are higher in HIV-infected persons and are associated with decreased NK cell populations (Douglas et al 2001). In addition, substance P has been shown to accelerate HIV replication in human peripheral blood monocyte-derived macrophages (Ho et al 1996). More research is needed on other possible pathways that may be responsible for conveying the effects of psychological factors on HIV disease markers.

Summary To conclude, existing research provides some evidence that psychosocial factors, such as chronic depression and stressful life events, may affect HIV disease progression. Research providing the strongest support for these conclusions includes: 1) long-term prospective studies; 2) studies examining the effects of chronic depression or those using statistical approaches that allow for time-varying psychological measures; and 3) studies of persons recently experiencing a major stressor (e.g., bereavement) or studies with interview-based approaches to assess life stress. It must be noted that the majority of the cited studies on psychological moderators of HIV infection have been conducted on men, primarily before the advent of protease inhibitors. Therefore, this review may not be generalizable to women or to those currently taking HAART. The findings from recent studies among female samples, however, have been consistent with those conducted among men. Future studies should focus on these understudied populations, especially among those taking HAART. In addition, research is needed to address some of the discrepancies in the past findings (e.g., inconsistent results across different disease outcomes [e.g., number and percentage of CD4, AIDS, mortality]). Despite studies showing that depression and stress may impact HIV disease progression, we know little about the biological mechanisms that might account for these relationships. There is some research to support the hypothesis that alterations in the HPA axis and the SNS might play such a mediating role; however, more evidence is needed to elucidate these complex biological relationships within the context of HIV infection. Furthermore, studies are needed on interventions aimed at modifying the deleterious effects of depression and stress among those infected with HIV. Cognitive behavioral stress management interventions and bereavement support groups have been shown to reduce distress and have a salutary effect on immune and health-related measures in HIV-infected patients (Goodkin et al 1998; Ironson et al 1994; Lutgendorf et al 1998; Mulder et al 1994). It is important for clinicians treating HIV-infected patients to screen patients for depression and to provide adequate treatment when warranted.

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Supported in part by National Institute of Mental Health Grants MH44618 and MH-33127, National Institute of Health (NIH) Grant RR00046, and NIH P30-HD37260 (University of North Carolina Center for AIDS Research). Aspects of this work were presented at the conference, “The Diagnosis and Treatment of Mood Disorders in the Medically Ill,” November 12–13, 2002 in Washington, DC. The conference was sponsored by the Depression and Bipolar Support Alliance through unrestricted educational grants provided by Abbott Laboratories, Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly and Company, Forest Laboratories, Inc., GlaxoSmithKline, Janssen Pharmaceutica Products, Organon Inc., Pfizer Inc., and Wyeth Pharmaceuticals.

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