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Published online before print June 2, 2008, 10.1097/PSY.0b013e318177353e
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Psychosomatic Medicine 70:569-574 (2008)
© 2008 American Psychosomatic Society

BIOBEHAVIORAL MECHANISMS

Behavioral Mediation of the Relationship Between Psychosocial Factors and HIV Disease Progression

Cheryl Gore-Felton, PhD and Cheryl Koopman, PhD

From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA.

Address correspondence and reprint requests to Gore-Felton, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Room 2315, Stanford, CA 94305-5718. E-mail: cgore{at}stanford.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 NOTES
 REFERENCES
 
The psychological and physical demands of coping with medication side effects and comorbid illnesses can be overwhelming and may influence behaviors, such as medication adherence, substance use, sexual risk behavior, and exercise that, in turn, affect health outcomes. Cross-sectional and prospective studies among diverse populations of persons living with HIV suggest that these behavioral mechanisms may be associated with HIV disease progression. The motivation to change behavior is often highest in the immediate aftermath of a stressor. However, over time the motivation to continue a particular behavior change is often challenged by habits, environmental influences, and psychosocial factors. Furthermore, a number of studies suggest that behavioral mechanisms may mediate the relationship between psychosocial variables (e.g., stress, depression, coping, and social support) and disease progression in HIV. Thus, developing clinical interventions that address these psychosocial factors and enhance protective health behaviors and reduce behaviors that convey risk to health are likely to lessen overall morbidity and mortality among patients living with HIV/AIDS.

Key Words: HIV • AIDS • behavioral mechanisms • psychosocial • disease progression

Abbreviations: HAART = highly active antiretroviral therapy; CAP = community-acquired pneumonia.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
NOTES
 REFERENCES
 
Formany patients, the development of highly active antiretroviral therapy (HAART) has meant improvement in health outcomes such that living with HIV/AIDS is experienced less as an acute stressor and more as a chronic, life-threatening disease (1). Although HAART has significantly improved the trajectory of morbidity and mortality rates associated with HIV/AIDS, maintaining high adherence and other health-enhancing behavior remains a challenge for many individuals who are faced with significant psychosocial stressors (2–4). The relationship between behavior and HIV progression is complex. Similar to other patients with chronic or terminal illnesses, individuals with HIV/AIDS often experience psychosocial challenges, such as social isolation, depression, and traumatic life events that can complicate the course of the disease (5). The psychological and physical demands of coping with medication side effects and comorbid illnesses can be overwhelming and may influence behaviors that affect health outcomes. Although the motivation to change health behavior is often highest in the immediate aftermath of a stressor, over time, behavior change is often challenged by psychosocial and other factors. Thus, understanding the behavioral mechanisms associated with HIV disease progression and how they may mediate the impact of psychosocial factors on disease progression is important for developing clinical interventions to reduce overall morbidity and mortality among patients living with HIV/AIDS.

This literature review focuses on representative research that indicates an association between behavioral mechanisms, psychosocial factors, and disease progression (Figure 1). Limited research demonstrates that psychosocial and behavioral factors (e.g., depression, stress, substance use, and alcohol use) may mediate the impact of clinical interventions on HIV disease progression. Research on how behavioral factors may mediate the effects of psychosocial variables on HIV disease progression is lacking. Therefore, we will first review relationships between disease progression and such health behaviors as treatment adherence, substance use, alcohol use, tobacco use, and sexual risk behavior. Second, we will summarize research on relationships between health behaviors and several psychosocial variables (e.g., depression, stress, social support, coping) that have been linked to HIV disease progression. Finally, we conclude with research directions and clinical implications.


Figure 18
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  		Figure 1. Behavioral mediation of psychosocial factors and HIV disease progression.

 

Behavioral Mechanisms That May Contribute to HIV Disease Progression
Treatment Nonadherence
Adherence to the treatment regimen (i.e., the match between the patient’s behavior and health care advice) (6) is important because it may prolong the disease-free period and overall survival. Suboptimal adherence can lead to drug resistance and poor response to treatment (7). Numerous studies have shown that low adherence is associated with faster disease progression (8–10). Adherence is affected by the complexity, intensity, and side effects associated with medication regiments (11,12) as well as a host of psychosocial factors, such as depression (13–15).

Illicit Drug Use and HIV Disease Progression
In 2005, injection drug use was associated with 25% of the AIDS diagnoses among men and 27% of the AIDS diagnoses among women (16). In vitro studies have demonstrated that opiates and cocaine up-regulate HIV-1 replication (17,18). Drug use may also directly contribute to immunosuppression (19). Some epidemiological research has demonstrated a relationship between drug use and HIV progression such that drug use was related to faster HIV decline. For example, in a prospective study among female and male drug users (20), crack cocaine use was independently associated with progression to AIDS. Similarly, Anastos et al. found that drug use (cocaine crack or heroin) was related to a greater risk of AIDS-defining illness and AIDS death in a large prospective cohort study (8). Furthermore, a prospective cohort study of 764 HIV-1 infected patients found that active drug use was significantly and positively associated with inferior virologic and immunologic responses to HAART compared with former- and nondrug users (21). The pathway or mechanism of how crack cocaine and other illicit drugs is related to faster progression to AIDS requires further scientific inquiry.

Drug use may indirectly contribute to HIV disease progression due to its association with other poor health habits. Crack cocaine users are more likely to be daily alcohol drinkers, smoke cigarettes, be homeless, and have tuberculosis (TB). The rates of TB may be higher among crack users because of the high incidence of homelessness, which increases the risk of exposure in shelters. Crack may also have direct effects on the lungs or indirectly by its association with other drug use, thereby facillitating faster AIDS progression (20).

Empirical evidence strongly indicates that drug use also affects adherence, thereby influencing HIV progression (12,22–24). There are, however, negative studies that have not found a relationship between drug use and adherence (25,26). The variability in findings is likely because of differences in the methodology to assess antiretroviral adherence and how drug use is defined (e.g., which drugs are assessed and variability in drug use measurement). For instance, the negative studies used a self-report measure in a cross-sectional survey design (25,26) in contrast to longitudinal approaches in studies demonstrating a relationship between substance abuse and adherence using a computerized assessment of adherence, i.e., the Medication Event Monitoring System (27,28). Furthermore, there are data suggesting that drug use patterns change over time, which has implications for how we measure drug use and adherence. For example, a longitudinal study examining the temporal relationship of drug and alcohol use on medication adherence among men and women receiving care in an inner-city clinic found changes in substance use were directly related to changes in antiretroviral therapy adherence (23). Participants who abstained from drug and heavy alcohol use were more likely to demonstrate improved adherence to antiretroviral therapy. In this same study, over two thirds of the participants changed their substance abuse status at least once during the 30 months of assessments, with decreases in substance use associated with improvements in adherence, greater viral suppression, and higher CD4+ cell counts.

Alcohol Use and HIV Disease Progression
Before the advent of HAART, there were no direct effects found between alcohol and disease progression (29). In the era of HAART, research indicated that there are likely direct and indirect effects of alcohol use among HIV-positive individuals. For example, a cross-sectional study of HIV-positive men and women with a history of alcohol problems found that individuals on HAART who reported any alcohol use had lower CD4+ cell counts and higher viral load compared with those individuals who did not drink alcohol (30). Similarly, Parsons et al. found a significant and positive relationship between the amount of alcohol consumed and viral load such that greater alcohol use was associated with higher viral load among HIV-positive men in New York City who had alcohol problems (31). The cross-sectional design of these studies makes the mechanisms for this association unclear. However, it is hypothesized that alcohol use may have direct effects on the immune system; there may be an interaction between alcohol use and antiretroviral medications; alcohol may exacerbate an underlying liver disease; or there may be behavioral effects on adherence that influence CD4+ count and viral load (30). Counter to the cross-sectional study findings, a HAART era prospective study on 595 HIV-positive men and women found no association between heavy alcohol use and CD4+ count or viral load among those on antiretroviral therapy, controlling for adherence and depression (32). However, alcohol consumption was associated with lower CD4+ count among those not on antiretrovirals. The inconsistent findings may be a function of behavioral changes over time (e.g., alcohol use patterns), and or physiological changes that occur over time that have differential affects on the interaction of antiretroviral therapy, alcohol use patterns, and HIV disease.

Tobacco Use and HIV Disease Progression
A study of 521 HIV-positive adults examined the effects of tobacco use on clinical outcomes (33). After matching individuals on HAART and the Centers for Disease Control and Prevention disease stage, individuals who were smokers were more likely to be hospitalized for a respiratory infection compared with nonsmokers. Moreover, after controlling for HAART, CD4+ count, and viral load, smokers were more likely to be hospitalized with Pneumocystis carinii pneumonia. Furthermore, individuals who smoked were twice as likely to be infected with community-acquired pneumonia (CAP) compared with nonsmokers and the risk was dose dependent such that the more cigarettes per day that were smoked, the greater likelihood of being diagnosed with CAP. Consistent with these findings, a study of 54 HIV-positive adults found that immune and virologic responses to HAART were decreased by 40% among smokers, suggesting that tobacco use may interact with antiretroviral metabolism (34).

Sexual Risk Behavior and HIV Disease Progression
Continued sexual risk behavior may have important consequences for the disease process and surrogate immune and viral markers. Infection with either sexually transmitted or blood-borne infectious agents may lead to immune stimulation and/or direct transactivation (i.e., an increased rate of gene expression) of HIV-replication (35). Sexual risk behavior among homosexual men with AIDS is associated with a greater risk for Kaposi’s sarcoma-associated herpes virus infection (36). Infection with multiple types of HIV strains, some of which may be multiple-drug-resistant viruses, also poses increased risk of disease progression (37,38).

Exercise and HIV Disease Progression
The pre-HAART era research found significant benefits of exercise on disease progression. The efficacy of exercise in reducing morbidity associated with cardiovascular disease, obesity, diabetes, and other chronic diseases is well documented (39,40). Similarly, studies among HIV-positive adults have found improvement in mood, muscle strength, and CD4 lymphocytes after 8- to 15-week exercise programs (41–43). A review on the effect of exercise and wasting—specifically, cachexia, which is described as the loss of lean body mass—found that resistance exercise training can increase muscle strength, bone density, and functional capacity and is an effective method for delaying HIV-related cachexia (44). Moreover, a longitudinal study from 1985 to 1991 among a cohort of homosexual men found that moderate physical activity was associated with an increase in CD4+ cell count, suggesting that exercise may slow HIV disease progression (45).

In the post-HAART era, fewer exercise studies have been conducted that examine the effect on disease progression. A systematic review and meta-analysis conducted by O’Brien et al. (46) examined studies published from 1980 to 2002 that were randomized clinical trials of aerobic exercise for a total of ≤12 weeks (except one study that was 24 weeks). Participants were ≥18 years and primarily male. A total of ten studies were analyzed and found that there was no statistically significant difference in CD4+ cell count between exercise and nonexercise groups. Three studies in the O’Brien et al. review were analyzed that looked at viral load, and similar to the CD4+ cell count no statistical differences were found between the exercise and nonexercise groups. These findings, along with research conducted pre-HAART, suggest that exercise is safe for HIV-positive adults. Moreover, in the era of HAART, aerobic exercise does not seem to have an effect on disease progression. However, for individuals who do not or cannot take HAART, exercise may be beneficial. It is important to note that the review is based on a limited number of studies. More research is needed that examines diverse types of exercise among men and women living with HIV/AIDS.

Behavioral Mediation of the Relationship Between Psychosocial Factors and HIV Disease Progression
Depression
Depression is one of the most common mental health disorders reported among individuals with chronic illnesses (47), and depression among adults living with HIV is well documented (48). Depressive symptoms have been shown to predict an increased risk of developing AIDS and HIV disease progression (49). Moreover, research with symptomatic HIV-positive men that examined a cognitive behavioral stress management intervention identified the reduction of depression as a likely mediator of the therapeutic effects on reconstituting immunity (50).

Although an association between depression and HIV disease progression may be due to the lack of a "protective" effect of positive affect or mood (51), it may also be partially mediated by behavioral mechanisms that include substance use and nonadherence. Depressed individuals may be more likely than others to turn to using alcohol and other drugs as a strategy to self-medicate (52). In turn, as noted previously, greater substance use is associated with poorer adherence and poor health outcomes for individuals living with HIV/AIDS. Depression may also affect HIV disease progression by undermining treatment adherence (10). There is a large literature showing that depression is associated with poor HIV treatment adherence (7). Recent studies examining the effects of depression on HIV disease progression have controlled for adherence and substance use (8–10,14,15,53), and yet still find a relationship between depression and HIV disease markers. Although these studies did not evaluate whether adherence or substance abuse affected these depression/disease relationships, it is clear that these behaviors did not wipe out the depression effects. More research is needed to delineate the behavioral pathways that may mediate the relationship between depression and AIDS progression.

Stress
Traumatic and other stressful life events are highly prevalent among persons who are HIV-positive (5). Childhood sexual abuse and other traumatic life events seem to be risk factors for sexual risk behavior and injecting and other drug use associated with HIV infection (54). Clinical evidence suggests that stressful life events predict more rapid HIV disease progression (49). For instance, research has found that, for every severely stressful life event per 6-month interval, the risk of early HIV disease progression doubled (55). In research on persons recently notified of HIV-positive serostatus, posttraumatic stress disorder symptoms of avoidance and intrusion were associated with greater distress, and avoidance was predictive of lower CD4+ percentages (56). Furthermore, both general perceived stress and the chronic stress of living in unstable housing conditions have been associated with physical health status in HIV-positive persons in the Deep South of the United States (57).

Although physiological changes associated with stress (e.g., neuroendocrine and sympathetic nervous systems) may account for the relationship between stress and HIV disease progression (58), behaviors associated with stress can also have deleterious effects on health outcomes. One route for stress to affect HIV disease progression may be through health behaviors. For example, many individuals who experience stress have poor exercise activity, use tobacco, alcohol, and other drugs (59). However, it is important to note that studies showing the effects of stress on HIV disease progression continue to demonstrate an effect of stress even after controlling for drug use (60) or adherence (61). Clearly, more research is needed to delineate the causal pathways of stress and disease progression in HIV disease.

Coping
Passive coping strategies, such as denial, have been associated with HIV-1 disease progression (62). Moreover, individuals who use more active coping strategies were less likely to develop HIV-related symptoms over a 1-year period, (63,64). Active coping would be expected to reduce disease progression among HIV-positive persons because such strategies would likely enable individuals to incorporate safer sexual behavior and develop behaviors that increase adherence to complex regimens in HAART therapy (10). Additionally, a study that examined the effect of coping on HIV disease progression at 6 and 12 months found that, among individuals with CD4+ cell counts between 299 and 499, emotional inexpressiveness and decreased recognition of needs and feelings were positively and significantly associated with HIV disease progression (65). Interestingly, for individuals with CD4+ cell counts of >500, there was no association found between coping style and disease progression. Taken altogether, these findings highlight the complexity of coping and its association to disease outcomes, underscoring the need to understand the contextual and temporal influences of this relationship. For instance, it is likely that the coping strategies that are beneficial early in one’s disease may become harmful as the disease progresses, requiring very different psychological resources to activate different behavioral responses. For individuals with HIV whose disease has progressed and requires regular medical monitoring and intervention, the psychological process of being aware of one’s needs may be a salient factor in activating adherence to medical treatment. For individuals with a robust immune profile, factors other than coping—such as alcohol or drug use—may be more salient for their disease trajectory.

Although it remains unclear what actually mediates the relationship between coping and disease progression, it is likely that certain behaviors are enacted by passive coping strategies, such as substance use, unsafe sex, missed appointments, and poor adherence to complex medication regimens.

Social Support
Potential sources of social support are often burdened and impaired by the high levels of stress in the lives of persons living with HIV (66). An AIDS diagnosis is associated with lower levels of practical and emotional support from family members (67,68). Leserman et al. found that social support was associated with slower progression to AIDS and a clinical AIDS condition (69). Furthermore, problems with inadequate social support may have physiological as well as psychological consequences. In general, greater social support has been associated with better immune system function (70,71). Among HIV-positive persons, those with less deterioration in CD4+ cell count were significantly more likely to report greater social support availability (71). Consistent with the research suggesting that more social support is associated with better immune function, bereavement, a loss of an important source of social support, has been associated with two functional immune decrements, namely, decreased natural killer cytotoxicity and decreased lymphocyte proliferative response to phytohemagglutinin (72). Social support has also been associated with treatment adherence (73). Furthermore, the social network’s influence on drug use has been well established (74). The research evidence identifies negative and positive influences as having high levels of drug use in a person’s social network that serve as a barrier to quitting drug use as well as being associated with sharing works, having sexual partners who inject drugs, and having unprotected sexual intercourse (75).

Research Directions
Prospective studies are needed to examine the behavioral mechanisms mediating the relationship between psychosocial factors and HIV disease progression. Further studies examining these mediating effects will increase our understanding of how psychosocial factors influence HIV disease progression (76). To date, there are compelling data demonstrating that psychosocial factors are correlated with behavior and that some behaviors affect HIV disease outcomes. Future research is needed that documents the temporal precedence of psychosocial factors to changes in behavior that, in turn, contribute to HIV disease progression. It is highly likely that in some circumstances, such as substance abuse and depression, we will not be able to determine temporal precedence because it will be difficult, if not impossible, to document whether depression preceded the substance use, or whether substance use preceded the onset of depression. Therefore, it may not be possible to determine true mediation in many circumstances.

The experimental literature that evaluates the effect of clinical interventions on HIV disease progression (77) has an important role to play in examining behavioral mediation between psychosocial factors and disease progression. If the intervention targets the psychosocial factors using an experimental design and the data indicate that behavioral change mediates the effect of the intervention on disease progression, then this is likely the best information that can be scientifically gathered on the behavioral mediation of psychosocial factors given the difficulty in assessing temporal precedence among these variables.

It is important to note that there is evidence suggesting that other factors not reviewed here (e.g., diet, nutrition, socioeconomic status) are also associated with HIV disease progression (78–80). It will be important for future studies to use complex models that examine these constructs across diverse populations.

Implications for Disease Management and Clinical Practice
The research reviewed here provides further support for the need to gain better understanding of the synergy between biological, psychological, and behavioral factors that contribute to disease progression. Such research is critical because incorporating approaches that influence the behavioral mechanisms associated with disease progression within standard treatment and care of HIV/AIDS patients may promote better health outcomes by reducing morbidity and mortality. Transforming how medicine views behavioral and psychosocial factors within the context of chronic illness undoubtedly means treating HIV from an interdisciplinary approach, which focuses appropriate attention on behaviors that affect disease course. As individuals live longer with HIV, interventions are urgently needed that consider the influence of time on health behaviors that pose significant risk to morbidity and mortality. Adherence to complex medication regimens are likely to be influenced by life events that change over time. Thus, clinical interventions need to be flexible so that they accommodate developmental changes and facilitate behaviors that promote positive health behaviors throughout the life span.


   NOTES
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 ABSTRACT
 INTRODUCTION
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REFERENCES
 
Received for publication June 7, 2007; revision received December 17, 2007.

Supported by Grant NIMH R01 MH072386 (PI: C.G.-F.).

DOI:10.1097/PSY.0b013e318177353e


   REFERENCES
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 INTRODUCTION
 NOTES
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