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Mindfulness meditation training effects on CD4+ T lymphocytes in HIV-1 infected

adults: A small randomized controlled trial

Brain, Behavior and Immunity

J. Creswell, F. Myers, W. Cole, & R. Irwin

University of California, Los Angeles

unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Abstract

Mindfulness meditation training has stress reduction benefits in various patient

populations, but its effects on biological markers of HIV-1 progression are unknown. The

present study tested the efficacy of an 8-week Mindfulness-Based Stress Reduction

(MBSR) meditation program compared to a 1-day control seminar on CD4+ T

lymphocyte counts in stressed HIV infected adults. A single-blind randomized controlled

trial was conducted with enrollment and follow-up occurring between November 2005

and December 2007. A diverse community sample of 48 HIV-1 infected adults was

randomized and entered treatment in either an 8-week MBSR or a 1-day control stress

reduction education seminar. The primary outcome was circulating counts of CD4+ T

lymphocytes. Participants in the 1-day control seminar showed declines in CD4+ T

lymphocyte counts whereas counts among participants in the 8-week MBSR program

were unchanged from baseline to post-intervention (time X treatment condition

interaction p=.02). This effect was independent of antiretroviral (ARV) medication use.

Additional analyses indicated that treatment adherence to the mindfulness meditation

program, as measured by class attendance, mediated the effects of mindfulness

meditation training on buffering CD4+ T lymphocyte declines. These findings provide an

initial indication that mindfulness meditation training can buffer CD4+ T lymphocyte

declines in HIV-1 infected adults.

Although great advances have been made in antiretroviral (ARV) treatment of

HIV-1 infection, there is still variability in treatment outcome (May et al., 2006).

Psychological stress may account for some of this variability, as animal and human

studies have demonstrated that stress accelerates HIV-1 disease pathogenesis and impairs

the biological impact of ARV treatment (for review, see Cohen et al., 2007; Cole et al.,

2001; Ironson et al., 2005). Consistent with this, recent studies indicate that behavioral

stress management interventions may improve biological indicators of HIV-1

pathogenesis (Antoni et al., 2006; Petrie et al., 2004, cf. Crepaz et al., 2008), but it is

unknown whether mindfulness meditation impacts HIV-1 progression (Ospina et al.,

2007; et al., 2003).

The Mindfulness-Based Stress Reduction (MBSR) program (Kabat-Zinn, 1982) is

a standardized and manualized 8-week mindfulness meditation training intervention that

has been shown to reduce stress and improve self-reported health outcomes in a variety of

patient populations (Brown et al., 2007). In the MBSR program, participants practice a

series of guided mindfulness meditation exercises in weekly classes and at home daily

(e.g., body awareness, mindful stretching, sitting meditation, and mindfulness in daily life

practices). It is thought that the MBSR program helps participants bring a more open and

receptive awareness to their present moment experiences in daily life, facilitating a

greater recognition and regulation of stress (Brown et al., 2007). Currently, few

investigations have examined the effects of MBSR on immune outcomes or biological

stress pathways, but initial studies in this area indicate that MBSR may have salutary

effects on antibody titer response to influenza vaccination (son et al., 2003),

cytokine signaling in cancer patients (Carlson et al., 2007; Carlson et al., 2003), and NK

cell numbers and cytotoxic activity in HIV patients ( et al., 2003). Further, some

recent evidence suggests that MBSR may reduce total daily salivary cortisol output at

follow-up (Carlson et al., 2007), an effect that may be consistent with stress reduction.

An initial pilot study of MBSR in HIV-1 indicated that mindfulness meditation training

can impact immune system function ( et al., 2003), but did not assess markers

of HIV-1 pathogenesis, such as CD4+ T lymphocytes and HIV viral load. Thus, a single

blind randomized controlled trial was conducted to test whether an 8-week MBSR

program buffers CD4+ T lymphocyte declines in a community sample of HIV-1 infected

adults.

Methods

Participants

Study participants were recruited through HIV/AIDS community agencies in Los

Angeles. To qualify for the study, participants had to be diagnosed HIV-positive for >6

months, English-speaking, and over age 18. In order to recruit a sample who was at risk

for stress-associated CD4+ T lymphocyte declines (Cohen et al., 2007), participants had

to report at least minimal symptoms of psychological distress at baseline as measured by

depressive symptomatology (>4 on the Patient Health Questionnaire-9(PHQ-9))(Spitzer

et al., 2000). Participants were excluded for any substance abuse or psychiatric treatment

in the past 30 days, were currently diagnosed with AIDS (or had CD4+ T lymphocytes

<200 cells/mm3), had hepatitis, or indicated a regular mind-body practice (e.g., tai chi,

meditation) in the past six months. A CONSORT flowchart (Figure 1) depicts the flow of

participants retained at each phase of the trial.

Procedure

All study procedures were approved by the UCLA IRB, and written informed

consent was obtained from all participants prior to baseline. Participants were enrolled

and completed the baseline assessment over a four-month period, and were then

randomized to either the 8-week MBSR or 1-day control intervention.

The 8-week MBSR program (Kabat-Zinn, 1990) included eight weekly 120-

minute group sessions, a day-long retreat in the seventh week, and daily home

mindfulness meditation practice. The group sessions consisted of instructor-guided

mindfulness body awareness activities, mindfulness meditations, mindful stretching, and

group discussions. A six-hour day-long retreat in week 6-7 of the MBSR program

focused on integrating and elaborating on the exercises the participants learned during the

8-week course. Finally, participants were instructed to practice 30 minutes of audioguided

mindfulness exercises each day at home during the eight-week program. The oneday

stress education MBSR program was a condensed version of the 8-week MBSR

program. Participants in this condition attended a day-long 6 hour seminar where they

received information, instruction, and practice in the same mindfulness practices taught

in the 8-week program, including group discussions. Instructors did not discuss or

encourage participants to start home or daily-life mindfulness practices in the one-day

MBSR condition. The one-day MBSR program was administered between weeks 4-6

during the 8-week program.

Post-intervention assessment of CD4+ T lymphocyte levels was completed for all

participants within two-weeks of the last session of the 8-week program. Participants

were enrolled on a rolling basis, and randomized in one of four cohorts between February

2006 and October 2007. A 2:1(8-week MBSR, one-day education) randomization

schedule was employed, and study assessment personnel were blind to participant

condition.

Measures

Peripheral blood CD4+ T lymphocyte levels and concentrations of HIV-1 RNA

were assessed at baseline and post-intervention. CD4+ T lymphocyte levels were

determined by flow cytometry and complete blood count by a licensed clinical reference

laboratory, and plasma HIV-1 RNA concentrations were assayed by an Amplicor HIV-1

Monitor assay (Roche Diagnostics, Indianapolis, Indiana). MBSR treatment adherence

was assessed by MBSR class attendance. A measure of total class attendance was

determined by summing the number of hours of MBSR class attended from attendance

sheets by study staff (2 hours for each MBSR class, 6 hours for the one-day MBSR

retreat, and 6 hours for the 1-day education intervention).

Statistical Analysis

Statistical analyses were conducted on the treatment participants (N=48), and on

the entire randomized sample (N=67). Treatment participants (N=48) were defined as

those who attended at least one study class. Data were analyzed using mixed effects

linear models treating study condition and time (baseline vs. post-intervention) as fixed

effects. Primary analyses modeled time as a repeated measure, subject condition, and a

time X treatment interaction term. Ancillary analyses with covariates and treatment

adherence modeled these variables as fixed effects predictors.

Results

Participants in both treatment arms indicated moderate psychological distress at

baseline (M=9.8, SD=3.7), and levels of psychological distress were not significantly

different between treatment groups at baseline (Table 1). The two treatment groups did

not differ on any other measured characteristics at baseline (Table 1). As shown in Table

1, control participants had slightly higher CD4+ T lymphocytes at baseline, greater ARV

use at post-intervention, and had a higher proportion of heterosexual participants,

although these differences did not reach conventional levels of statistical significance (all

p?s > .08). These differences would be expected to favor the control group and thus could

not account for any positive intervention effects observed. It is also possible that these

differences could reflect different study populations due to study dropout rates or other

factors. To minimize any potential confounding effects, ancillary analyses were

conducted (described below) to control for ARV use, number of days between the pretest

and post-test assessments, sexual orientation, and age.

The average participant in the study was male, African American, homosexual,

unemployed, and not on ARV medication. Participants on ARV medications indicated an

average self-reported adherence of M=.45 (SD=.76) missed doses in the past week at

baseline and M=.71 (SD=1.14) at post-intervention. Participants who completed all

assessments (N=38) were compared to study dropouts (N=29) on all baseline

characteristics. Study dropouts were significantly younger than study completers,

t(65)=2.26, p=.03, but no other significant differences emerged. Dropout rates in the

treatment sample in the 8-week MBSR condition (N=8) and the 1-day control condition

(N=1) were not significantly different (c2(1)= 2.10, p =.15). Although not significant, a

greater proportion of participants in the 8-week condition dropped out, and is likely due

to the more demanding and time intensive nature of this program.

To determine the effects of the MBSR and control programs, mixed effects linear

models analyzed log-transformed and raw CD4+ T lymphocyte counts in both the

treatment (N=48) and randomized (N=67) samples. A mixed effects linear model on the

treatment sample revealed a significant time X treatment interaction on log10CD4+ T

lymphocytes, F(1,45)=5.70, p=.02 (Figure 2) and raw (non log-transformed) CD4+ T

lymphocytes (Table 2), F(1,44)=5.03, p=.03. Specifically, the 8-week MBSR participants

had a raw mean increase of 20 CD4+ T lymphocytes, whereas the 1-day control

participants had a raw mean decrease of 185 CD4+ T lymphocytes from baseline to postintervention (Table 2). Analyses of the entire randomized (N=67) sample, which included participants who never received any treatment, showed the same pattern of results,

F(1,57)=3.15, p=.08. The potential clinical impact of this finding was assessed by

counting participants with CD4-defined AIDS (<200 cells/mm3) at post-intervention. No

participants had CD4-defined AIDS at baseline; 14% (N=2) of participants in the control

condition reached CD4-defined AIDS at post-intervention compared to 0% (N=0) of

participants in the 8-week MBSR condition.

Ancillary analyses using mixed effects linear models explored the role of

confounding factors on the time X treatment CD4+ T lymphocyte effect. The inclusion of

ARV medication status at baseline and post-intervention (binary variables: on or off

ARVs) as covariates did not affect the strength of the time X treatment interaction on

CD4+ T lymphocytes (F(1,45)=5.50, p=.02), indicating that mindfulness meditation

training buffers CD4+ T lymphocyte declines in participants both on and off ARV

treatment regimens. Additional analyses explored the potential confounding effects of

variability in the number of days between the baseline CD4+ T lymphocyte measure and

the initiation of the 8-week MBSR class, sexual orientation (0=heterosexual,

1=homosexual or bisexual), and participant age in three separate mixed effects linear

models. Similar to ARV medication status, the time x treatment interaction on log10CD4+

T lymphocytes remained statistically significant after control for variability in the number

of days between the baseline measure and the initiation of the 8-week MBSR class

(F(1,45)=5.66, p=.02), sexual orientation (F(1,45)=5.64, p=.02), or participant age

(F(1,45)=5.51, p=.02).

Mediation analyses were consistent with the hypothesis that mindfulness

meditation treatment adherence explained the observed time X treatment interaction on

log10CD4+ T lymphocytes. Treatment participants attended 12.5 (SD=7.6) class hours in

the 8-week MBSR program and 6 (SD=0) class hours in the 1-day education control. As

shown in Figure 3, a series of mixed effects linear models assessed statistical mediation

(Baron and Kenny, 1986). In a model with the treatment sample (N=48) where class

attendance and the time X treatment interaction were entered simultaneously, MBSR

class attendance predicted greater CD4+ T lymphocytes at follow-up (b=.014, t(74)=2.09,

p=.04), and the path between the time X treatment interaction and log CD4+ T

lymphocytes was no longer significant (b=.06, t(56)=.56, p=.58). This finding indicates

that the frequency of class attendance could potentially account for as much as 2/3 of the

total effect of the experimental conditions on CD4+ T lymphocytes.

As previous findings have found effects of behavioral stress management in

reducing HIV RNA levels in participants with detectable levels of HIV RNA at baseline

(Antoni et al., 2006), exploratory analyses examined the effects of mindfulness

meditation training on HIV RNA levels in the sub-sample of participants with detectable

baseline levels of HIV RNA (N=30). No differences in baseline HIV RNA levels were

observed between the 8-week MBSR (M=46,880 copies/mL, SD=12,830) and 1-day

control sub-sample (M=12,700 copies/mL, SD=25,660) participants with detectable

levels of HIV RNA (t(28)=1.19, p=.24). Consistent with the limited statistical power

available in this small sub-sample, no significant effects were observed on HIV RNA

(time X treatment interaction p=.41).

Discussion

CD4+ T lymphocyte depletion is a hallmark characteristic of HIV-1 pathogenesis

and progression to AIDS. The present study provides initial evidence that a behaviorally

targeted mindfulness meditation stress-reduction program can buffer CD4+ T lymphocyte

declines in an ethnically diverse sample of HIV-1 infected adults. Additional analyses

suggested that the mindfulness meditation treatment effects on CD4+ T lymphocytes are

independent of ARV treatment status. These data are consistent with the possibility that

mindfulness meditation training may have direct effects on CD4+ T lymphocyte

distributions (e.g., via effects on haematopoiesis, T-cell redistribution dynamics, or T-cell

turnover in lymphoid tissues) (McCune, 2001). A second possibility is that mindfulness

meditation training effects on CD4+ T lymphocytes may be explained in part through

reductions in HIV RNA levels. A number of studies provide strong links between stress

and HIV viral replication (e.g., Cole et al., 1998; Sloan et al., 2007), and stress

management programs have been shown to reduce HIV RNA levels in some studies (e.g.,

Antoni et al., 2006; Petrie et al., 2004). The present study was not appropriately powered

to examine the effects of mindfulness meditation training on HIV RNA levels, which is

an important pathway that should be examined in future studies with larger samples.

The major limitations of the study include a small sample size and high attrition

rates, no long-term follow-up assessments, and an insufficient sample size to determine if

mindfulness meditation training impacts HIV-1 RNA levels. Additionally, although not

significantly different at traditional statistical thresholds, 1-day control participants had

higher numbers of CD4+ T lymphocytes at baseline compared to 8-week MBSR

participants. It is possible that this baseline difference could be driving the overall effects

described in this report, so an additional ANCOVA analysis compared the 8-week and 1-

day groups on post-test log10CD4+ T lymphocytes, while controlling for baseline levels

of log10CD4+ T lymphocytes (in participants with complete pre and post-test data,

N=39). Although underpowered, this analysis was consistent with the mixed model

findings indicating that 1-day control participants had lower CD4+ T lymphocytes than

8-week MBSR participants at post-test (p=.06). Despite these limitations, the present

findings provide a first indication that a low-cost group-based mindfulness meditation

training program can buffer CD4+ T lymphocyte declines, and that this occurs in direct

proportion to the amount of mindfulness meditation training received. Although more

studies are needed to determine the clinical impact of this program, these findings suggest

that mindfulness meditation training may be a beneficial adjunct for stressed HIV-1

infected adults.

In summary, an 8-week mindfulness meditation and stress reduction program can

buffer CD4+ T lymphocyte declines in a diverse community sample of HIV-1 infected

adults. Well-controlled studies with larger samples are needed to determine if

mindfulness meditation training interventions can positively impact biological indicators

of immunopathogenesis in HIV-1 infection, but the present findings provide a promising

first indication that mindfulness meditation may have benefit as a complementary adjunct

treatment for HIV-1.

Acknowledgements

J.D. Creswell had full access to all of the data and takes responsibility for the integrity

and accuracy of the data. We thank the UCLA Mindful Living Project team and our

MBSR instructors (C. Baum, H. Blumenfeld, and G. Kamler) for their assistance in this

study. This study was supported by a National Institute of Mental Health (NIMH)

postdoctoral research fellowship (T32MH-019925-09) to the first author, a seed grant

from the Cousins Center for Psychoneuroimmunology at UCLA, and the UCLA General

Clinical Research Center (NIH/NCRR #M01-RR00865). No financial interests or

conflicts of interest are declared.

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