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Role of Depression, Stress, and Trauma in HIV Disease Progression

From the Departments of Psychiatry and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Address correspondence and reprint requests to Jane Leserman, Department of Psychiatry, CB 7160, Medical School Wing C, Room 233, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7160. E-mail: JLes{at}med.unc.edu

	ABSTRACT

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Despite advances in HIV treatment, there continues to be great variability in the progression of this disease. This paper reviews the evidence that depression, stressful life events, and trauma account for some of the variation in HIV disease course. Longitudinal studies both before and after the advent of highly active antiretroviral therapies (HAART) are reviewed. To ensure a complete review, PubMed was searched for all English language articles from January 1990 to July 2007. We found substantial and consistent evidence that chronic depression, stressful events, and trauma may negatively affect HIV disease progression in terms of decreases in CD4 T lymphocytes, increases in viral load, and greater risk for clinical decline and mortality. More research is warranted to investigate biological and behavioral mediators of these psychoimmune relationships, and the types of interventions that might mitigate the negative health impact of chronic depression and trauma. Given the high rates of depression and past trauma in persons living with HIV/AIDS, it is important for healthcare providers to address these problems as part of standard HIV care.

Key Words: HIV • AIDS • depression • stress • trauma

Abbreviations: HAART = highly active antiretroviral therapies; CHIP = Coping in Health and Illness Project; WIHS = Women’s Interagency HIV Study; CHASE = Coping with HIV/AIDS in the Southeast.

	INTRODUCTION

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Earlyon in the HIV epidemic, researchers were interested in testing hypotheses relative to the role of stress and depression in HIV disease course due to the broad evidence linking psychosocial variables with changes in cellular immunity (1–5). If psychosocial disturbances could alter immune responses, then it made sense to examine whether stress and depression might affect an immune-based disorder like HIV, a disease where the variability in disease progression was largely unexplained and the population was at high risk for adverse mental health. Today, despite advances in the treatment of HIV, there continues to be considerable unexplained variability in the course of this disease. With a growing proportion of the HIV population being women and persons in poverty, we see high rates of depression and past trauma among individuals infected with HIV (6–8). In this review, we will examine the evidence that depression, trauma, and stressful life events are associated with decrements in HIV disease markers, both before and after the advent of HAART.

To ensure an exhaustive literature review, PubMed was searched for all English language articles from January 1990 to July 2007 including "HIV" and the following key words: depressive, depression, stress, distress, trauma, and bereavement. Our review focuses on longitudinal studies (1 year) from before and after the HAART era. A study was considered HAART era (post 1996) if at least a large minority of patients were on HAART during part of the data collection. The studies on depression predicting HIV disease progression are summarized in Table 1, and studies on the role of stressful life events and trauma in predicting changes in HIV disease course are summarized in Table 2.

Depression and HIV Disease Progression Before HAART
Because HIV infection tends to advance very slowly, the most compelling evidence for the role of depression in this disease comes from studying cohorts over long time intervals. In addition, because depressive symptoms change over time, the most methodologically sound studies account for changes in depression (chronicity or time-varying scores) rather than focusing on a single baseline measure. Consider these issues as we review the available literature, beginning with studies conducted before the HAART era.

The San Francisco Men’s Health Study, a 9-year longitudinal study of about 400 asymptomatic HIV-infected gay men, found that those who were depressed at study entry progressed to AIDS on average 1.4 years sooner than those who were not depressed (9). These findings were not altered when adjusting for baseline demographic variables, CD4 T lymphocyte count, HIV-related medical symptoms, and health habits. Prior analyses at 5.5 years showed that baseline depression was related to decline in CD4⁺ T lymphocytes, although not progression to AIDS or mortality (10). Analyzing recurrent depression in this cohort at 7 years, Mayne et al. found that men with elevated depressive affect at every visit had a 67% greater risk of mortality compared with those without such symptoms (11). These analyses adjusted for antiretroviral use and several disease markers. Another analysis of these San Francisco data showed that positively worded items on the depression scale (e.g., hopeful, happy) were better predictors of survival than negative items (e.g., sad, lonely) (12).

Baseline depression was not significantly associated with progression of HIV infection during 8 years following 1339 gay men in the Multicenter AIDS Cohort Study (13); however, there was an increase in depression during the 6 to 18 months before an AIDS diagnosis (14). Although these data have not been examined for the effects of chronic depression, a reanalysis at 13 years showed that somatic symptoms of depression (fatigue, poor appetite, trouble concentrating) at baseline were associated with shorter survival time, although not shorter time to AIDS, after controlling for antiretroviral medications (15). Three additional studies before the HAART era had mixed findings when examining depression at study entry. Patterson and colleagues found a relationship between baseline depression and shorter time to death, but not to change in CD4⁺ count or AIDS (16). Golub et al. found that baseline depression was associated with more than twice the risk of AIDS progression, but no association with mortality (17). Finally, a 1-year study did not show an association of depression with CD4 count, CD4%, or CD4/CD8 ratio (18).

The Coping in Health and Illness Project (CHIP) examined the change in depressive symptoms every 6 months for up to 9 years in 96 initially asymptomatic HIV-infected gay men (19–21). For every cumulative average increase of one severe depressive symptom, the risk of AIDS was doubled at 5.5 years (19), and the risk of a clinical AIDS condition, but not AIDS, was more than doubled at 9 years (20). These findings adjusted for demographic variables, number of antiretroviral medications, and baseline values of HIV viral load and CD4⁺ lymphocyte count. Similarly, a recent 6- to 8-year study of 996 Tanzania women without access to HAART showed that depression measured over time was associated with a 61% increased risk of clinical progression and over twice the hazard of death (22).

In summary, the most consistent evidence for the relationship between depression and HIV disease progression comes from studies examining the chronic effects of depression or depressive symptoms. Limitations to interpreting the research reported thus far include inability to generalize to women and nongay males, and all studies being conducted before widespread access to HAART. Will depressive symptoms be an important predictor of HIV disease progression in the era of more potent antiretroviral medications, and when more diverse populations are included? Recently, studies are addressing these questions.

Depression and HIV Disease Progression in the HAART Era
Ickovics and colleagues examined the health effects of chronic depression in HIV-infected women (n = 765) during a 7-year period when HAART began to be available (23). Women with chronic depressive symptoms were about two times more likely to die from AIDS than those who never experienced depression; the effects of depression were particularly pronounced among women who began the study with low CD4⁺ cell counts. Depression was also associated with greater decline in CD4⁺ count. These analyses controlled for baseline CD4⁺, HIV viral load, HIV-related symptoms, antiretroviral therapy, and HAART use. In a recent reanalysis of these data, Ickovics and colleagues found that women with more positive psychological resources (e.g., positive affect, finding meaning, and positive HIV expectancy) had greater decreases in AIDS-related mortality (24). For a more thorough discussion of the role of positive affect in HIV disease progression, see the article by Ironson and Hayward in this issue (25).

The Women’s Interagency HIV Study (WIHS), a recent 7.5-year investigation of 1716 women from five US cities, showed that those with chronic depressive symptoms were more likely to die from HIV (13%) than those with few or no depressive symptoms (6%) (26). In addition, women who received mental health services were significantly less likely to experience AIDS-related mortality. These findings were maintained when controlling for demographic variables, illegal drug use, HIV medication use during the study (e.g., HAART, monotherapy), and baseline CD4, viral load, and HIV symptoms. Depression (time-varying) was associated with poorer virologic response, and greater risk of immunological failure, AIDS-defining illness, and all-cause death among a subset of the WIHS women initiating HAART use (27).

In studying 490 HIV-infected men and women, Leserman and colleagues found that each standard deviation increase in depressive symptoms was related to a 49% increased risk of AIDS mortality, controlling for demographic variables, CD4, viral load, and antiretroviral therapy (28). No effect of depressive symptoms on all-cause mortality was found. Finally, Ironson and colleagues found that cumulative depression and hopelessness were associated with decreases in CD4 count and increases in viral load in a 2-year study of 177 HIV-infected patients, controlling for HAART and medication adherence (29).

Several studies have examined depression at the time of HAART initiation in persons previously naïve to this medication. Depression at initial HAART use was associated with: a) over five times the risk of clinical progression to AIDS (30), b) slower virologic suppression (31), and c) shorter survival (32). In addition, cumulative depression (with and without somatic symptoms) was associated with progression to AIDS during 6.5 years, adjusting for demographic variables, nonadherence, CD4 cell count, and virological response (30).

Despite the decreasing prevalence of opportunistic infections during the HAART era, we continue to find consistent evidence that chronic depression is associated with clinical and immunological progression of HIV/AIDS. Table 1 shows that a more robust relationship between depression and HIV disease progression is found when analyzing the chronic effects of depression in larger studies performed over longer time intervals. Despite this association, the question remains whether depression puts HIV-infected persons at greater risk for disease progression or whether changes in disease may be associated with increased risk of depression.

Direction of the Relationship Between Depression and Disease Change
Studies have tried to address the chicken-egg issue of whether depression is a predictor or result of disease progression by measuring depression in the time intervals before HIV-related clinical or immunological changes. This approach helps to establish that the depressive symptoms occurred before changes in disease status. Researchers have noted that depression scores tend to be elevated in the year preceding AIDS-related death (14,26). If disease changes are gradual, however, this strategy may not address the time-ordering of events. In reexamining data from the CHIP study, Leserman showed that AIDS clinical symptoms and CD4⁺ cell count did not predict major depression (33); however, depressive symptoms did predict development of AIDS (19) and an AIDS clinical condition (20). This provides some evidence that depression may be more likely to lead to clinical disease change than vice versa.

Stress/Trauma and HIV Disease Progression Before HAART
Another approach to determining if psychological factors may affect HIV disease progression has been to examine the impact of stressful events and trauma on changes in disease markers. The advantage of studying persons experiencing stress or trauma is that the causal direction of the relationship between stressful events and HIV disease change may be less ambiguous than the effects of depression, depending on the nature of the stressors studied. Generally, the term "trauma" is reserved for severe stressful life events included in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (e.g., sexual and physical abuse or assault, unexpected deaths) or that tend to be on the severe end of stressful events and difficulties (e.g., childhood neglect, parental drug abuse) (34).

Bereavement
Older studies before HAART have examined the stress of bereavement in HIV-infected persons, given that the gay population was at high risk for having a partner or close friend die. In a study of 85 HIV-infected gay men, those whose close friend or partner died of AIDS had more rapid decline in CD4⁺ count during a 3- to 4-year follow-up (35). These findings were not explained by differences in health habits or antiretroviral medication use; however, bereavement did not predict progression to AIDS or mortality. Bereaved men also have been shown to have increased serum neopterin (an immune activation marker associated with increased risk of AIDS), and decreased natural killer cell cytotoxicity and lymphocyte proliferative response to phytohemagglutinin compared with nonbereaved persons (36,37). Finding meaning in the loss of a loved one or having less distress when notified about HIV-positive serostatus have also been associated with slower progression of HIV (38,39).

Stressful Life Events, Trauma, and HIV Disease Progression
CHIP investigators have consistently reported adverse immunological and health effects of stressful life events during 9 years following a cohort of 96 gay men (19–21,40–42). The CHIP measure of stressful life events was based on interviewer contextual ratings of 111 possible stressful events and difficulties (e.g., deaths, change in employment, relationships, finances, and health). It excluded stresses that could have resulted from disease progression (e.g., retirement due to HIV worsening), and omitted patient’s ratings of distress to reduce the possibility that worsening disease could lead to poor coping and thus higher stress scores. Higher cumulative-average stressful event score was predictive of faster progression to AIDS (decline in CD4⁺ T lymphocytes <200 and/or AIDS indicator condition) during 5.5- (19), 7.5- (21), and 9-year follow-up (20). For every increase in cumulative-average stress equivalent to one severe stressor, the risk of AIDS was about doubled, and the risk of developing an AIDS clinical condition was about tripled (20). At study end, 74% above the median in stress progressed to AIDS compared with 40% below the median. Cox regression analyses adjusted for demographic variables, baseline CD4⁺ cells and viral load, number of antiretroviral medications, and serum cortisol.

In a 1-year study of 618 HIV-infected youths, two or more stressful life events (e.g., parent’s major illness, death, lost employment and desertion, sibling’s death, housing change) was associated with almost a three-fold increased risk of immune suppression (decline in CD4%), controlling for demographic and disease-related variables (43). Trauma exposure (sexual/physical assault, death of child), particularly among those with posttraumatic stress disorder (PTSD), was associated with a greater decrease in the CD4⁺/CD8⁺ ratio during 1 year following 67 asymptomatic HIV-infected African-American women (44). Older studies using short follow-up periods, baseline stress measures, and/or self-rating methods to assess life stress have generally not shown an association of stress with reduction in CD4⁺ T lymphocyte counts or HIV disease progression (16,18,45). The lack of stress effects in the study by Patterson et al. is of note, given the longer follow-up period (up to 5 years); however, minor and moderate stresses before study entry may be unlikely to affect HIV disease course years later (16). These studies concerning the role of bereavement, stress, and trauma are limited in that they were all completed before the widespread use of HAART.

Trauma and HIV Disease Progression After HAART
Recently, CHASE (Coping with HIV/AIDS in the Southeast) investigators studied 490 HIV-infected men and women from five rural southern states followed by medical records for up to 41 months (28,46). Patients with more categories of lifetime trauma (e.g., 15 types of trauma including sexual/physical abuse, childhood neglect, murder of family member) had faster all-cause and AIDS-related mortality (28). For those above the median in trauma, the all-cause death rate was 3.54 per 100 person-years compared with 1.72 for those below the median. Another analysis of CHASE data showed that trauma was associated with faster development of an opportunistic infection or AIDS-related death (46). The vast majority of the traumatic events in the CHASE data occurred 2 years before study entry. In the only other study examining stressors in the HAART era, Ironson et al. showed that HIV-infected persons with more life events (measured by questionnaire) had greater increases in viral load, but not change in CD4, during a 2-year follow-up (29).

In summary, Table 2 shows that the more consistent findings regarding the health impact of stress and trauma in HIV come from studies using interview-based stress ratings measured over time or from studies of major lifetime trauma. It may be that traumatic events continue to exert effects over long periods of time, whereas stressful events (e.g., change in employment, relationship break-up) have greater impact if we consider cumulative events.

Clinical and Policy Implications
Past research has consistently shown that persons infected with HIV have very high rates of past trauma, depression, and PTSD compared with the general population (6,47–49). Our review has shown that these high rates of dysphoria are highly relevant risk factors, given that depression and stressful events are important predictors of HIV disease course—both before and after HAART availability. Furthermore, studies also link depression to premature HAART discontinuation and HAART nonadherence (32,50–52)—factors associated with poor health outcome (53). There is also evidence that those who receive mental health services are less likely to die from AIDS-related causes (26), and that psychological interventions (e.g., cognitive behavioral stress management) may improve depression, anxiety, and nonadherence as well as affect HIV health outcomes (54,55). These findings underscore the importance of psychological/psychiatric screening, treatment, and referrals to address depression and the psychological sequelae of past trauma as part of standard HIV care.

Despite the benefits of psychological and psychiatric intervention, data from a national probability study of HIV-infected men and women indicate that about half of the depressed patients remained undiagnosed and untreated (56,57). Case managers may help to fulfill these unmet needs of HIV-infected clients by providing greater access to mental health counseling (58). HIV treatment often focuses exclusively on monitoring the fluctuation of numbers, such as CD4 lymphocyte count and viral load. Although these measures are critical to HIV care, the current review points to the clinical importance of monitoring mental health and past trauma history, giving credence to these psychosocial risk factors.

Summary
To conclude, existing research provides support for the hypotheses that psychosocial factors, such as chronic depression and stressful events, can affect clinical and immunological progression of HIV/AIDS, even in an era with decreasing prevalence of opportunistic infections. We know little about the biological mechanisms that may account for these relationships. There is some research to support the theory that alterations in the hypothalamic-pituitary-adrenal axis and sympathetic nervous system may play such a mediating role (59); however, more evidence is needed to elucidate these complex biological relationships within the context of HIV infection. In addition, behavioral factors, such as medication nonadherence and other unhealthy habits (e.g., substance abuse, risky sex), may also play a role in mediating these psychoimmune relationships (60).

Further studies are needed on interventions aimed at modifying the deleterious effects of depression and trauma among those infected with HIV. Will psychological and psychiatric interventions help to mitigate some of the negative health consequences of depression and trauma? We need more information and better dissemination of information about what psychological and psychiatric treatments might be beneficial for HIV-infected persons presenting with depression, past history of trauma, and PTSD. It is critical that clinicians treating HIV-infected patients recognize depression and trauma as risk factors for poor health outcome and thus screen and treat patients for these problems.

	NOTES

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Received for publication May 21, 2007; revision received August 9, 2007.

Supported in part by Grant R01 AT002035 from the National Institute of Health. The author has no conflicts of interest.

DOI:10.1097/PSY.0b013e3181777a5f

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