Neil Schneiderman, Ph.D., Michael Antoni, Ph.D., and Gail Ironson, M.D., Ph.D.

Investigators in the Behavioral Medicine Research Center at the University of Miami have examined relations among stress, immunity and secondary prevention of HIV/AIDS for more than a decade. Initially, as part of Miami?s Center for the Biopsychosocial Study of AIDS, the behavioral medicine research team examined relations among stress, neuroendocrine and immunologic patterns in seronegative and asymptomatic HIV-1 seropositive gay men. Subsequently, with program project, individual research project, and research training grant support from the National Institute of Mental Health (NIMH), the team's research focus was expanded to examine symptomatic as well as asymptomatic HIV+ individuals, long term survivors of AIDS and HIV+ minority women.

At the outset of our investigations we suspected that the potential exists in HIV spectrum disease for patients to remain free of symptoms for a prolonged period and that appropriate patient management could delay the onset of AIDS and ameliorate its course. For these reasons we thought that it would be useful to view HIV as a chronic disease and that group- based cognitive behavioral stress management (CBSM) might play an important role in improving quality of life and slowing symptom onset. First, we thought that CBSM could improve the HIV-infected person's quality of life by decreasing the distress and depressed affect associated with having a chronic and likely fatal disease, increasing the use of acceptance and positive reframing strategies, and increasing or maintaining social support. Second, we believed that the psychosocial intervention would facilitate adherence to good health practices and appropriate utilization of the health care system by decreasing the use of avoidance and denial as coping strategies and using problem-focused as opposed to emotion-focused coping in situations where problem solving skills could be useful. Third, we suspected that a CBSM intervention, including relaxation training, might be able to attenuate the impact of stressors upon an already compromised immune system and in so doing might slow the course of immune decline that is observed in HIV spectrum disease.

The recent advent of the protease inhibitors and triple combination therapies has brought about important improvements in the health care of AIDS patients. Now more than ever before HIV/AIDS can be viewed as a chronic disease in which patient management is important. And now more than ever psychosocial interventions should be a part of this management. For once patients are given protease inhibitors, medication protocols must be rigidly followed with respect to drug schedules and food intake or the virus may mutate and become drug resistant. Not only can this eliminate the usefulness of the particular protease inhibitor being used, but also the utility of other related compounds to which cross-resistance has developed. Consequently, CBSM protocols that provide information, skills and support to patients can facilitate adherence to medication protocols. In our research we have shown that CBSM can decrease denial and depressed affect, which in turn can facilitate adherence to medical treatment regimens. Improvements in immune function that have been associated with our CBSM protocols, raise the interesting question of whether CBSM interventions can help reconstitute the compromised immune system once pharmacologic agents have contained the virus.

Individuals suffering from HIV face continual psychosocial stressors including potential or actual social isolation, overwhelming medical costs and concern over physical deterioration. Inadequate coping with those demands may lead to depressed affect, hostility, reduced social support utilization, high-risk sexual behavior, alcohol and/or drug abuse, impaired immune functioning and possibly accelerated disease progression. Conversely, good coping skills together with a high sense of coping self-efficacy may be associated with good psychological adjustment and stress resistance, which might reduce disease progression.

Before turning to our CBSM studies let us examine how the responses made to a naturalistic stressor may be associated with disease progression. In one of our studies, Gail Ironson and colleagues examined the psychological predictors of 2-year disease progression in gay men after finding out their HIV serostatus. Psychological and immune status of asymptomatic gay men who did not know their HIV serostatus was monitored during the five weeks before and after serostatus notification. The strongest and most consistent psychological predictor of immune status and disease progression in our HIV+ gay men was the use of denial to deal with a seropositive diagnosis. Here, denial is defined as believing and acting as if the diagnosis of HIV seropositivity had not been made. In our study, denial remained a significant predictor of disease progression even after controlling for CD4 number at entry. Furthermore, change in denial (five weeks post-diagnoses minus pre-diagnosis) was significantly correlated with the CD4 number one year later; one-year immune status was significantly correlated with two-year disease progression. Although based upon a small number of subjects, the study demonstrated significant relations between an important psychological variable on the one hand and immune measures as well as HIV-1 disease progression on the other.

An important issue to be considered, is how denial might be related to disease progression. Likely candidates worthy of being studied include a lack of doing things necessary to keep oneself healthy, such as not keeping physician appointments, failing to obtain updated information about AIDS treatments and not adhering to medication regimens. Further investigation also needs to determine whether denial is related to continuing unsafe sex or to using recreational drugs and alcohol. In addition, denial as used in the present context (i.e., response to a seropositive diagnosis) appears to be an immature defense mechanism that may be correlated with poor mental health and inadequate ability to handle adverse situations well. Finally, denial may preclude the individual from dealing with attendant emotional reactions, thus failing to express anger, sadness, and other dysphoric emotions. In our intervention studies, we have been examining the relationship between denial and other psychosocial and immune variables.

In our first CBSM intervention study conducted upon asymptomatic gay men, Michael Antoni and members of our group randomized subjects into a CBSM condition or an assessment-only control group five weeks before notification of HIV-1 antibody status. Seventy-two hours before and one week after serostatus notification, blood samples and psychometric data were collected. Participants in the CBSM condition met semiweekly for 10 weeks in small groups led by two co-therapists. In one 90-minute weekly session, the men received training in cognitive restructuring, assertiveness skills and behavior change strategies along with basic information on the psychosocial, social and physiological aspects of stress responses, the nature of HIV-1 transmission and associated risk behaviors, and a description of various safer sex behaviors. During these sessions participants were encouraged to generate examples of recently experienced stressors and to demonstrate the use of CBSM strategies as responses to these stressors by way of role play with other group members. In an additional 45-minute session held each week, subjects received training in progressive muscle relaxation, autogenic training and imagery. Because a key part of the CBSM intervention included home practice of relaxation exercises, participants were required to self-monitor and record their daily practice frequency.

Blood samples and psychometric data were collected 72 hours before and one week after serostatus notification. Both treatment and control participants received their serostatus notification and immediate counseling from a licensed social worker. One major finding of the study was that seropositive controls showed significant increases in depressed affect pre- to post-notification, whereas seropositives receiving CBSM did not. A second major finding of the study was that seropositive CBSM participants revealed significant increases in CD4 and natural killer cell (CD56) counts as well as an increase in proliferative responses to the plant mitogen phytohemagglutinin (PHA) whereas controls showed slight decreases or no change in these measures. Thus, the CBSM intervention appeared to buffer the dysphoric impact of an HIV+ diagnosis and modestly increased CD4 number.

The most up-to-date version of the CBSM protocol appears in Stress Management for HIV: Clinical Validation and Intervention Manual by Antoni, Schneiderman and Ironson (in press). It is the first volume in the Society of Behavioral Medicine?s research-to-practice guidebook series and provides the rationale, validation data, manual and workbook for the intervention program. In the initial study, participants were seen semiweekly. During more recent investigations, participants attended one weekly two-hour session involving both stress management and relaxation training. Also, in the initial study the participants in the control condition attended only assessment sessions. In some of our more recent investigations participants in the control condition undergo a 10-week waiting period; after the final assessment, participants are offered a one-day didactic and experiential stress management workshop emphasizing the same concepts as those presented in the CBSM intervention group.

In a recent study conducted by Susan Lutgendorf and collaborators, we tested the effects of our CBSM intervention in HIV+ gay men whose disease had progressed to a symptomatic stage. This study did not involve serostatus notification and the men were randomized into the CBSM intervention or to the modified wait list control group. The CBSM intervention significantly decreased dysphoria as measured by the Beck Depression Inventory and anxiety as measured by the Profile of Mood States. Individuals who practiced relaxation more consistently had significantly greater drops in depression scores over the intervention period.

In a subsequent analysis, Lutgendorf and colleagues examined the relative contribution of changes in coping skills and social support over the course of the 10-week intervention period to reductions in dysphoria, anxiety, and distress-related symptoms. We found that participants in the intervention condition showed significant improvement in cognitive coping strategies involving positive reframing and acceptance, as well as in total social support. In contrast, members of the wait-list control condition showed decrements or no change in these coping abilities. Improved cognitive coping abilities, specifically, acceptance of the HIV infection, were strongly related to lower dysphoria, anxiety and total mood disturbance in both conditions. Changes in social support and in cognitive coping strategies appear to mediate the decreases in distress noted as a consequence of the intervention. These results suggest that cognitive coping strategies and social support factors, particularly perceived social support, can be modified by psychosocial interventions and may be important determinants of psychological well-being and quality of life during symptomatic HIV infection.

Each of our studies thus far has shown that CBSM can alleviate depressed affect in HIV+ gay men. In our studies involving HIV serostatus notification, Antoni and colleagues also found that CBSM led to significant increases in CD4 number and in lymphocyte proliferation to PHA; Esterling and coworkers reported that the intervention led to decreased Epstein Barr Virus (EBV) and Human Herpes Virus-Type 6 (HHV-6) antibody titers. Because of evolving evidence that EBV may represent a cofactor in the development of AIDS, through expression of the CD4 receptor on EBV-infected B-lymphocytes, and that co-infection of CD4 cells by HHV-6 and HIV can aggravate HIV-induced lymphocytolysis, stress-induced reactivation of EBV and HHV-6 may have possible negative consequences in HIV-infected individuals.

Although speculative, it is possible that the apparent effects upon EBV and HHV-6 induced by the CBSM intervention may be due to reductions in psychological distress, to the normalization of cellular immune status as shown by Antoni and coworkers, or to some combination of the two. In any event, the data suggest that in addition to decreasing dysphoria, CBSM in asymptomatic HIV+ gay men is associated with modest increases in CD4 number and improved immune surveillance against other viral pathogens. These findings are further supported by the report of Lutgendorf and collaborators that the decreased dysphoria induced by the CBSM intervention in symptomatic HIV-infected men was accompanied by decreased genital herpesvirus, herpes simplex virus-type 2 (HSV-2), immunoglobulin G antibody titers. This suggests that decreasing mood disturbances in HIV-infected persons may influence their ability to survey viruses that can contribute to an increased risk of opportunistic infections.

During the past decade our group has carried out a number of psychosocial intervention studies with HIV-infected individuals. Most of our published experience has involved CBSM in HIV+ gay men. The most consistent findings with regard to the psychological effects of the interventions have been: (a) decrease in distress and depressed affect; (b) decrease in the use of avoidance and denial as coping strategies; (c) increase in the use of acceptance and positive reframing strategies; and (d) increase or maintenance of social support. Based upon conceptualization of HIV/AIDS as a chronic disease and the need for patients to adhere rigidly to medication protocols, the use of CBSM with emphasis upon developing skills that will facilitate medication adherence, would appear to be quite valuable. To the extent that CBSM has been shown to improve surveillance of latent herpes viral infections that could have clinical significance, further research is needed to study the role that such interventions could have in slowing disease progression.

Although space precludes our discussing our studies using other behavioral treatment modalities (e.g., exercise) or other populations, it should be noted that shifting demographic patterns of the HIV/AIDS epidemic make it imperative to develop techniques to help women of color manage their disease. This has been especially pertinent to us, because in a study examining the effects of stress on immunity in African American women co-infected with HIV and sexually-transmitted viruses, Diedre Byrnes and other colleagues in our group have found that elevated life events are associated with decreased natural killer cell toxicity in women co-infected with HIV and human papillomavirus, an important precursor of cervical cancer. With this in mind, Debra Greenwood has joined us in successfully adapting our CBSM intervention for low socioeconomic status African American women. And in order to examine the generality of our CBSM intervention in minority women, Stephen Weiss and other members of our group are conducting a CBSM multi-site study on women with AIDS in Miami, Newark and the Bronx.

In summary, CBSM appears to have a significant role to play in the management of HIV spectrum disease. This includes ameliorating distress, improving patient adherence to medical regimens, and facilitating the efforts of HIV-infected women and men to cope effectively with their chronic disease. The results should be seen in increased quality and quantity of life.