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Depressive Symptoms and Cervical Neoplasia in HIV+ Women with Human Papillomavirus Infection


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1 DEPRESSIVE SYMPTOMS AND CERVICAL NEOPLASIA IN HIV+ WOMEN WITH HUMAN PAPILLOMAVIRUS INFECTION By STACY MARIE DODD A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2007

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2 2007 Stacy Marie Dodd

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3 To Jeriann Dodd

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4 ACKNOWLEDGMENTS First, I thank Dr. Deidre Pe reira for her mentorship, guida nce, and support throughout the many phases of this project. Her depth of knowle dge, insightful advice, and passion for research has been instrumental in the completion of this work. I thank Dr. Michae l Antoni, the principle investigator on this study, for allowing me to pa rticipate in this research. Additionally, I extend my appreciation to Ms. Sally Je nsen, who has served as an ex cellent role model and provided guidance throughout this process. I would like to thank Ms. Ilona Buscher, Dr. Michele Peake, Ms. Trudi Simon, Dr. Mary Ann Fletcher, and Dr. Kevin Maher at the University of Miami for their involvement in this study. I also acknowle dge the members of my committee, Dr. Samuel Sears, Dr. Dawn Bowers, and Dr. Stephen Boggs. I would like to thank my family, and specifica lly my parents, for their endless support. Without my mother and father non e of this would have been po ssible. I thank my mother for being my inspiration for pursuing research in this field. I woul d also like to thank my friends and classmates for their guidance and support as well as camaraderie throughout this process. I extend my great appreciation for all of the wo men who participated in this research. I wish them the best.

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5 TABLE OF CONTENTS ACKNOWLEDGMENTS...............................................................................................................4 LIST OF TABLES................................................................................................................. ..........7 ABSTRACT....................................................................................................................... ..............8 CHAPTER 1 INTRODUCTION..................................................................................................................10 Epidemiology of HIV............................................................................................................ .10 Pathophysiology of HIV/AIDS...............................................................................................10 HIV/AIDS Classification........................................................................................................11 HIV and Human Papillomavirus............................................................................................12 Psychoneuroimmunology and CIN.........................................................................................13 Depression and HIV............................................................................................................. ..14 Current Study.................................................................................................................. ........15 2 METHODS........................................................................................................................ .....17 Design......................................................................................................................... ............17 Participants................................................................................................................... ..........17 Procedures..................................................................................................................... ..........18 Screening Visit................................................................................................................18 Psychosocial Interview....................................................................................................19 Statistical Procedures......................................................................................................... .....19 3 RESULTS........................................................................................................................ .......21 Demographics................................................................................................................... ......21 Health Behaviors............................................................................................................... .....21 Health Status.................................................................................................................. .........22 Depressive Symptoms............................................................................................................22 Relations between Depressive Symp toms and HIV-Related Immunity.................................22 Relations between Biobehavioral Va riables and Cervical Neoplasia.....................................23 Relations between Depressive Symp tomatology and Cervical Neoplasia.............................23 4 DISCUSSION..................................................................................................................... ....29 Study Limitations.............................................................................................................. ......31 Future Directions.............................................................................................................. ......32

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6 LIST OF REFERENCES............................................................................................................. ..35 BIOGRAPHICAL SKETCH.........................................................................................................41

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7 LIST OF TABLES Table page 1-1 CDC classification of HIV/AIDS......................................................................................16 3-1 Comparison of continuous demographic a nd health variables in participants who provided full and partial data.............................................................................................25 3-2 Comparison of categorical demographic a nd health variables in participants who provided full and partial data.............................................................................................25 3-3 Predicting presence of cervical ne oplasia from depressive symptoms..............................26 3-4 Predicting presence of cervical neoplasia from cognitive/affective depressive symptoms....................................................................................................................... ....27 3-5 Predicting presence of cervical neopla sia from somatic depressive symptoms................28

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8 Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science DEPRESSIVE SYMPTOMS AND CERVICAL NEOPLASIA IN HIV+ WOMEN WITH HUMAN PAPILLOMAVIRUS INFECTION By Stacy Marie Dodd May 2007 Chair: Deidre Pereira Major: Psychology Prior work has related elevated life stress to greater risk of cervical neoplasia in women coinfected with human immunodeficiency virus (HIV) and human papillomavirus (HPV). This study investigated associations between depressive symptoms (i ndependent of life stress and other possible confounders) and cervical neoplasia in women with HIV and HPV infection. Participants for this study were 54 HIV+HP V+ women; most were African American. Participants underwent a colposcopy, HPV scr eening, Papanicolaou smear, and cervical biopsy to determine study eligibility. Eligible participants then completed the Beck Depression Inventory (BDI). Scores on the BDI were us ed as a whole and were also divided into cognitive/affective symptoms and somatic symptoms. Hierarchical logistic regression analysis revealed that women who reported more depressi ve symptoms had marginally greater odds of presenting with cervical neoplasia, OR = 1.32, p = .062. While cognitive and affective depressive symptoms were not significantly associated with gr eater odds of presenting with cervical neoplasia, women who reported more soma tic depressive symptoms had greater odds of presenting with cervical neoplasia, OR = 2.29 p = .022, even after controlling for biobehavioral risk factors for cervical neoplasia (HIV viral lo ad and high-risk HPV) a nd recent negative life events. Thus, women who reported more somatic depressive symptoms had greater odds of

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9 presenting with cervical neoplasia These findings may suggest th at screening HIV+ women for somatic depression may help identify those at risk for cervical neoplas ia. In addition, these findings suggest that future research on depr ession in medical populat ions should not ignore somatic depressive symptoms, as they may have important implications for health outcomes.

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10 CHAPTER 1 INTRODUCTION Epidemiology of HIV Human immunodeficiency virus (HIV) is the virus that causes acquired immunodeficiency syndrome (AIDS) HIV and AIDS are serious gl obal health threats. In 2003, an estimated 4.8 million people worldwide became newly infected with HIV. Approximately 37.8 million people are currently living with HIV. Over 20 million have died from the disease since the epidemic began in 1981; 2.9 million died in 2003 alone (Joint United Nations Programme on HIV/AIDS [UNAIDS ], 2004). In the United States, 43,171 new AIDS cases were reported to the Center for Disease Contro l and Prevention (CDC) in 2003. Of these, 21,304 (49.3%) cases were diagnosed in African Americans compared to 12,222 (28.3%) cases diagnosed in Caucasians. AIDS-related mortality is also higher among African Americans than Caucasians. Death rates associated with AIDS are nearly 8 times higher in African American men than Caucasian men. For women the dispar ity was even larger: death rates for African American women due to AIDS are nearly 13 times higher than those for Caucasian women (National Center for Health Statistics, 2005). In 2002, HIV/AIDS was the leading cause of death in African American women between the ages of 25 and 34 (Anderson & Smith, 2005). These discrepancies are even more pronounced since Af rican Americans constitute only 12.3% of the U.S. population (U.S. Census Bureau data fo r 2000, 2006). Although HIV and AIDS are serious health threats for all Americans, the virus and disease have a di sproportionately large impact on the African American community. Pathophysiology of HIV/AIDS Infection with HIV occurs through mucosal cont act with bodily fluids infected with the virus. This occurs through sexual intercourse or the sharing of cont aminated needles. In the past,

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11 HIV infection occurred following medical tran sfusion of infected blood products; this has become rare subsequent to blood screening proc edures to identify infected blood. Approximately 2-6 weeks following initial infection, most (but not all) individuals expe rience an influenza-like illness corresponding with the init iation of HIV-specific cellular immune responses (Nadler, 2006). During this time, cytotoxic T-cells (CD8 T-cells) are activated and work to kill HIV infected cells and HIV antibody production occu rs (Janeway, Travers, Walport & Shlomchik, 2001). After the primary infection stage, HIV enters the second stage of inf ection, often referred to as the asymptomatic stage. Though individu als in this stage gene rally do not express any clinical symptoms, the virus continues to repl icate and CD4 T-cell count s continue to decline (Nadler, 2006). One of the primar y factors influencing the amount of time an individual remains in the asymptomatic stage is the initial effec tiveness of the immune response to contain the infection. The HIV viral load that is established subsequent to initial in fection remains fairly stable over several years, and those with the highe st viral loads generally have faster progressing HIV infection (Nadler, 2006). For most indivi duals, this second st age of HIV infection eventually progresses to clinical AIDS, which is characterized by low CD 4 cell counts and/or the development of an AIDS-defining illness, as described below. HIV/AIDS Classification In 1993, the CDC revised the classification system for HIV/AIDS. According to the revisions, HIV/AIDS is classifi ed using three ranges of CD4 cell counts and three clinical categories. The three ranges of CD4 cell c ounts used to classify HIV in fection are 500 cells/L or greater (Category 1), 200-499 cel ls/L (Category 2), and less than 200 cells/L (Category 3). Individuals in Category 3 are clas sified as having developed AI DS, regardless of whether they

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12 have developed an AIDS defining condition. Ca tegory determinations are made based upon the lowest accurate CD4 cell count for that individua l, which is not necessarily the most recent cell count obtained (CDC, 1992). The three clinical categories of HIV/AIDS ar e Category A, B, and C. An individual is categorized as being in Category A, or asymptomatic HIV, if they have never experienced a symptomatic AIDS condition or an AIDS-defini ng illness (described below). Category B, or symptomatic HIV, is assigned to individuals who have experienced a symptomatic condition occurring in an HIV infected individual that is ei ther attributed to the HI V infection or indicates a deficit in cell-mediated immunity, or conditions th at have a clinical cour se that is complicated by the HIV infection. These do not include conditions designated as AIDS-defining illnesses. Category C, or clinical AIDS, is reached when an individual experiences an AIDS-defining illness as defined by the CDC. Classification of the clinical categories are based upon the history of HIV progression, thus once an individual meets criteria for a category they cannot move back into a previous category, even if the symptoms or illness placing them in the category is resolved (CDC, 1992). Based upon the three CD4 cell count categories and the three clin ical categories, there are nine mutually exclusive categories for the stag ing of HIV/AIDS, ranging from A1-C3 (Table 12). Categories A3, B3, C3, C1, and C2 confer a diagnosis of AIDS. HIV and Human Papillomavirus HIV infection may have a different course in women compared to men. Specifically, several opportunistic illnesses are more common, harder to treat, or occur exclusively in women with HIV as compared to their male counterpa rts. Examples include disorders of the upper genital tract, such as pelvic inflammatory diseas e, as well as disorders of the lower genital tract, such as cervical intraep ithelial neoplasia (CIN) (CDC, 1992). CIN is the pre-malignant phase of

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13 cervical cancer that is initiated and prom oted to cervical cancer by oncogenic Human Papillomavirus (HPV) infection, including HPV 16 and 18 infections. HPV is one of the most common sexually transmitted inf ections in the United States. Among immunocompetent women with HPV infection, adequate ce llular immune responses, most not ably T helper type 1 (Th1) cell immune responses (Scott, Stite s, & Moscicki, 1999), will survey the virus before it promotes the pre-malignant or malignant transformation of cells (Munoz et al., 2003). However, HPV infected women with suppressed cellular immune responses, such as women with immunodeficiency due to HIV infection, are not able to mount an adequate immune defense against HPV, resulting in pe rsistent and severe HPV infection and risk for malignant transformation of cells. Additi onal risk factors for CIN and cervical cancer among women with HIV include degree of immunosupp ression (low T helper/inducer lymphocyte [CD4+CD3+] cell counts) (Phelps et al., 2001; Davis et al., 2001), tobacco smoki ng (Hocke et al., 1998), and uncontrolled HIV viral load (Davis et al., 2001). Psychoneuroimmunology and CIN Pyschoneuroimmunology (PNI) is th e investigation of the re lations among psychosocial variables, neuroendocrine and immunologic f unctioning, and health outcomes. Research investigating psychosocial variab les and the presence and/or pe rsistence of CIN has yielded inconsistent results. Previous research has shown that poorer ps ychological well-being (greater pessimistic attitude, greater negative life event st ress) is associated with lower cell-mediated and natural immunity (Byrnes et al., 1998), greater number of genital herpes recurrences (Pereira et al., 2003b), and greater odds of progr ession and/or persistence of cer vical neoplasia (Pereira et al., 2003a) in women with HIV and HPV infections. In contrast, other re searchers have reported no associations between CIN progr ession or regression with negativ e life events, lack of social support, or coping style (Tiersma et al., 2005; Tiersma et al., 2004). However, no research to

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14 date has explored whether other common and treatable psychological conditions, such as depression, are associated with cervical neoplasia in women with HIV and HPV infections. Depression and HIV The relationship between depression and health status in HIV+ wo men is particularly important to examine for several reasons. De pressive symptoms and disorders are common among individuals with HIV infectio n. Studies have shown that nearly half of individuals with HIV infection meet diagnostic cr iteria for depression (Chandra et al., 1998). HIV+ women may be at particularly high risk of experiencing depressive sympto ms. Studies have shown that women in the general population experience major depression twice as often as men (Weissman & Oflson, 1995), and women infected with HIV e xperience major depressi on significantly more often than healthy women (Morrison et al., 2002). In addition, HIV+ women experience depression at rates twice that of HIV+ men (Evans et al., 2002). Notably, depressive symptoms in HIV+ individuals are associated with more rapid decline of CD4+CD3+ cell counts (Rabkin et al., 1991; Lyketsos et al., 1993; Sahs et al., 1994; Vedhara, Schifitoo, & McDermott, 1999; Burack et al., 1993; Ickovic et al., 2001), decreased natural kille r (NK) cell activity, increased HIV viral load, and greater risk of HIV related mortality (Burack et al., 1993; Ickovics et al., 2001; Mayne et al., 1996; Leserman et al., 1999). Depressive symptoms are also associated with faster development of any AIDS defi ning condition (Leserman et al., 2002). In spite of this research, no research to our knowledge ha s investigated the possible relationship between depressive symptoms a nd cervical neoplasia, a female-specific HIV associated opportunistic illness. This relationship is of particular intere st, because susceptibility to depression is elevated among women experi encing high life stress (Kendler, Karkowski, & Prescott, 1999) and individuals who are dispositionally pessi mistic (Beck, 1967; Pyszcynski, Holt, & Greenberg, 1987), two psychosocial fact ors previously associated with lowered

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15 immunity and progression and/or persistence of cervical neoplasia in HIV+ HPV+ women (Byrnes et al., 1998; Pereira et al., 2003). Current Study The purpose of the current study was to dete rmine whether recent depressive symptoms were associated with the presen ce of cervical neoplasia in a sample of primarily Black/African American women with HIV and HPV infections r ecruited for a trial examining the effect of a cognitive behavioral stress mana gement (CBSM) intervention on health (e.g., cervical neoplasia) and quality of life outcomes. It was specifica lly hypothesized that wome n with greater recent depressive symptomatology would have greater odds of cervical ne oplasia at study entry. Given that HIV-related symptoms and medication si de effects may be confounded with somatic symptoms of depression (Blaney et al., 2004; Jones, Beach, & Forehand, 2001), we also examined whether greater cognitive/affective symptoms of depressi on, specifically, were associated with greater odds of cervical neoplasia.

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16Table 1-1 CDC classifi cation of HIV/AIDS. Clinical Categories CD4 Cell Categories A (Asymptomatic HIV) B (Symptomatic HIV) C (AIDS defining illness) 1 500 or greater cells/ L A1 B1 C1 2 200-499 cells/L A2 B2 C2 3 less than 200 cells/L A3 B3 C3 Note: Categories A3, B3, C3, C1 and C2 receive a diagnosis of AIDS.

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17 CHAPTER 2 METHODS Design The current study utilized a cros s-sectional design. Fifty-four women co-infected with HIV and HPV underwent a colposcopy, HPV testing a nd subtyping, a peripheral venous blood draw, urine collection, and a 60-90 minute psychos ocial interview assessing mood and health behaviors. Statistical analyses examined the relationships between depressive symptomatology and the presence or absence of cervical neoplasia at study en try, while controlling for known biobehavioral risk factor s for cervical neoplasia. Participants Participants for this study were recruited as part of a longitudinal National Cancer Institute (NCI) funded study investigating th e effects of a cognitive-behavioral stress management (CBSM) intervention on the health a nd quality of life of women with HIV at risk for cervical cancer (PI: Michae l H. Antoni, Ph.D., 5 P50 CA 084944-05). Inclusion criteria were: (a) HIV+ women ages 18 to 60 years old, (b) history of at least 2 Papanicolaou smears indicating low grade squamous intraepithelial le sions (LSIL) or 2 cervi cal biopsies indicating CIN I in the 2 years prior to study entry, and (c) fl uency in spoken English. Exclusion criteria were: (a) 2 or more negative Papanicolaou smear s in the 2 years prior to study entry, (b) any history of high grade SIL (HSIL) or any history of CIN II, CIN III, or invasive cervical cancer, (c) any diagnostic or treatment procedures for CI N in the 6 months prior to study entry, (d) life expectancy < 12 months as determined by the st udys research nurse, a nd (e) current major, severe psychiatric illnesses that would interfere with the ability to provide valid psychosocial assessment data (e.g., suicidality, psychoticism, HIV dementia).

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18 Procedures Participants for this study were recru ited through Special Imm unology Clinics at the University of Miami/Jackson Memorial Hospital s. Patients at the Special Immunology Clinics were initially screened based on medical record data to determine whether they met basic eligibility requirements If a patient passed the preliminary eligibility screening, a researcher approached her during her visit to the clinic and explained th e study. Patients that were interested in participating in the study were scheduled to come in for a formal screening appointment. Screening Visit At the formal screening appointment, the study was explained in more detail and informed consent was completed. In additi on, the participant provided information on her gynecologic history, underwent a psychological screening, was pr ovided an educational module regarding colposcopies and a colposcopy was performed. The colposcopy was comprised of a Papanicolaou smear, colposcopic-guided cervical biopsy, and cervical swab for the detection and subtyping of HPV infection. Based on the results of the colposcopy, participants were classified as being positive or negative for cervical neoplasia at study entry. Hybrid Capture (HC) II assay (Digene Corporation, Gaithersburg, MD) was used to classify HPV subtypes as intermediate to high risk HPV (oncogenic subtype s) or low risk HPV subtypes. Immediately following the colposcopy, participants were administered th e Psychosocial Effects of Abnormal Pap Smears Questionnaire (PEAPS-Q Bennetts et al., 1995) to measure distress related to the colposcopy. Participants also underwent a peripheral venous blood draw in order to measure CD4+CD3+ cell counts and plasma HIV viral load. At the end of this visit, particip ants were given urine collection materials and instructions on collecting urine before their next visit. They were then

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19 contacted approximately one week later with the results of the screening and to inform them of whether or not they were ultimately e ligible to participate in the study. Psychosocial Interview If the participant was eligible for study part icipation after the formal screening, she was scheduled for another visit. At this visit, participants comp leted a psychosocial assessment interview. This interview included the B eck Depression Inventor y (BDI Beck, Ward, Mendelson, Mock & Erbaugh, 1961) and a genera l demographic questionnaire, among other psychosocial measures. The BDI is a 21-item se lf-report questionna ire that measures symptoms of depression. The BDI has been used extensivel y in previous research investigating depressive symptoms in HIV+ populations (Castellon, Hinkin, Wood & Yarema, 1998; Ferrando, Rabkin, de Moore & Rabkin, 1999; Judd et al., 2005; Laperriere et al., 2005; Weiser et al., 2006). Questions on the BDI assess both cognitive and aff ective (e.g., sadness, hopelessness) as well as somatic (e.g. fatigue, weight change) depressive symptoms. Thus it is possible to create scale scores from the BDI, which measure an indivi duals levels of cognitive/affective and somatic depressive symptoms independently. Statistical Procedures Results presented in this paper are base d upon cross-sectional psychosocial (i.e., BDI scores) and biological (i .e., cervical neoplasia) data. We st arted by examining relations between potential demographic and biobehavi oral control variables and cervical neoplasia in this sample. We then examined the relationship between rece nt depressive symptoms and the presence of cervical neoplasia in women with HIV and HPV infection using hier archical logistic regression. Regression equations contained two blocks of predictor variables: the first block consisted of traditional, well-established risk factors for cer vical neoplasia in HIV+ women (CD4+CD3+ cell count, HIV viral load, HR-HPV infection, and to bacco smoking) (Davis et al., 2001; Hocke et

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20 al., 1998; Phelps et al., 2001), and the second bloc k consisted of our psychosocial predictor of interest scores on the BDI. Tw o hierarchical logistic regressi on equations were analyzed. The first equation contained scores from all 21 items of the BDI. The second equation contained scores from only the cognitive/affective items of the BDI (i.e., BDI items 1 15). The criterion in both equations was presence () or abse nce () of cervical neoplasia by histology (cervical biopsy) at study entry. If a cervical biopsy was clinically contraindicated for a particular participant, the pres ence or absence of squamous intraepithelial lesions (SIL) by cervical cytology (Papanicolaou sm ear) at study entry was used.

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21 CHAPTER 3 RESULTS Demographics Sixty-six women met study criter ia and were enrolled in this study. The results reported here are based on 54 participants who provided full psychosocial, colposcopic, and immune data. Results of t-tests and chi-square analyses revealed that participants who provided complete data did not differ significantly (p > .05) from those w ho had incomplete data in age, yearly income, years of education, ethnicity, mar ital status, presence of neoplasia presence of high-risk HPV, HIV stage, or CD4+CD3+ cells/mm3. (Tables 3-1 & 3-2). The 54 participants who provided full data ranged in age from 18-45 years (M = 30 years, SD = 8.5 years). The majority of the women were non-Hispanic Black/African American (85.2%), with the remainder of the sample bei ng comprised of Hispanic Caucasian (9.3%), nonHispanic Caucasian (3.7%), and other (1.9%). The women had an average yearly income of $11,601 (SD = $8,089), and averaged 11.6 years of education (SD = 1.23 years). The majority of women in the study (55.6%) we re single/never married. Of the remaining 44.4%, 20.4% were married or in an equivalent relationship and 24% were separated, divorced, or widowed. Health Behaviors Seventy-two percent of the women who part icipated in this study were taking highly active anti-retroviral therapy ( HAART) at the time of study entr y. Self-reported adherence to HAART was significantly negatively correlated with HIV viral load, r = -.413, p = .011. Nearly 60% of the participants reported never having smoked. Of the remaining women who did report a history of smoking (N = 22), pack-years of smoking ranged from 6 5,110 (M = 1,904, SD = 1,880).

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22 Health Status Colposcopic-guided cervical biopsy reveal ed that 44 women (81.5%) presented with cervical neoplasia at study entry, while 10 wome n (18.5%) did not show evidence of cervical neoplasia. HPV screening and typing revealed that 42 wome n (77.7%) tested positive for intermediate or HR-HPV types. Twenty-three women (42.6%) had Category A (asymptomatic) disease at study entry. Thirteen women (24.1%) had Category B (sym ptomatic) disease, and 17 women (31.5%) had Category C (clinical AIDS) disease. The mean CD4+CD3+ cells/mm3 was 455.43 (SD = 285.47). Eight women (14.8%) had CD4+ CD3+ cell counts below 200 cells/mm3, 27 women (50%) had cell counts between 200 and 500 cells/mm3, and 19 women (35.2%) had cell counts above 500 cells/mm3. Depressive Symptoms Possible scores on the BDI range from 0-63, with higher scores indicating more depressive symptoms reported. The women in this study scor ed between 0-44 on the full BDI, with a mean of 8.6 (SD = 9.81). Previous research with HIV populati ons has utilized a BD I cutoff score of 10 to indicate depression (Laperrier e et al., 2005), thus the average score for women in this study was below depression cutoffs on the BDI. Twen ty-one women (39%) in the study obtained BDI scores of 10 or greater. Relations between Depressive Symptoms and HIV-Related Immunity The results of correlational analyses demons trated that neither total BDI scores nor cognitive/affective BDI scores were correlate d with CD4+CD3+ cell counts; however, women with greater somatic BDI scores had si gnificantly lower CD4+CD3+cell counts, r = -.286, p = .036. BDI scores (total, cognitive /affective, and somatic) and HIV viral load were not correlated (ps > .05).

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23 Relations between Biobehavioral Va riables and Cervical Neoplasia Correlational and chi-squared analyses were co nducted to determine whether variables that have been shown to be risk factors of cervi cal neoplasia in HIV+ women (HIV viral load, presence of HR-HPV subtypes, CD4+CD3+ cell c ounts, and tobacco smoking) were related to cervical neoplasia in this sample. HIV viral load (r = .30, p = .027) and presence of HR-HPV subtypes ( 2 [1] = 5.48, p = .019) were significantly related to the presence of neoplasia. Despite the fact that CD4+CD3+ cell counts and tob acco smoking were not significantly related to neoplasia, all four potential risk factors were entered as contro l variables into Block 1 of the regression equations as a conservative measure based on their strong associations with incidence of neoplasia in previous research. Relations between Depressive Symptomatology and Cervical Neoplasia Using scores from the entire BDI as the predictor of interest, a marginally significant relationship emerged between greater depressive symptomatology and gr eater odds of cervical neoplasia, OR = 1.19, 95% CI = .0.98 1.45, p = .084. The overall model was significant, 2 (5) = 16.72, p = 0.005 (Table 3-3). Subsequently, the relationship between only the cognitive/affective items of th e BDI, specifically, and cervical neoplasia was examined. Contrary to our hypothesis, th ere was no significant relations hip between cognitive/affective symptoms of depression and th e odds of cervical neoplasia, OR = 1.18, 95% CI = 0.95 1.48, p = 0.181 (Table 3-4). Given that there was (a) a marginally signifi cant relationship between scores on the entire BDI and cervical neoplasia and (b) no significan t relationship between the cognitive/affective scores and neoplasia, we explored the possibility that scores on the somatic items of the BDI (BDI items 16-21) were related to greater odds of cervical neoplasia. Hierarchical logistic regression analysis revealed that women who reported higher levels of recent somatic depressive

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24 symptomatology had over two-fold gr eater odds of cervi cal neoplasia, OR = 2.21, 95% CI = 1.03 4.73, p = 0.042. The overall model was significant, 2 (5) = 19.77, p = 0.001 (Table 3-5). In order to ensure that the relationship between r ecent somatic depressive symptoms and cervical neoplasia was independent of life st ress, a factor previously demons trated to be associated with the progression and/or persistence of cervical neoplasia in HIV+ wo men over time (Pereira et al., 2003), we also controlled for the im pact of recent negative life event stress using an abbreviated 10-item version of the Life Experiences Su rvey (LES) (Sarason, Johnson, & Seigel, 1978) described in detail elsewhere (P ereira et al., 2003). A significan t relationship remained between greater somatic depressive symptoms and greater odds of cervical neoplasia after controlling for risk factors for neoplasia and life stress, OR = 2.19, 95% CI = 1.01 4.74, p = 0.046 (not shown). Finally, to investigate whethe r an individual somatic depres sive symptom was driving the association between somatic de pressive symptomatology and cervical neoplasia, correlational analyses were conducted on each of the somatic BDI items and neoplasia. Results of these analyses showed that only the BDI question re garding difficulty sleeping was significantly correlated with cervical neoplasia (r = .313, p = .021). However, when the BDI question regarding sleep was removed from the hierarchi cal logistic regression, the remaining somatic depressive symptoms continued to be significantly associated with greater odds of presenting with cervical neoplasia (OR = 2.27, p = .049, 95% CI = 1.01-5.12). Thus, it appears that the constellation of somatic depressive symptoms and not necessarily difficulty sleeping is associated with greater odds of pr esenting with cervical neoplasia.

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25Table 3-1 Comparison of continuous demogra phic and health variables in participants who provided full and partial data. Potential control variable Respondents mean ( SD ) Non-respondents mean ( SD ) t Df p -value Age (years) 30.04 (8.45)35.0 (7.55)1.93865 0.057 Yearly income ($) 11,601 (8,089)11,575 (9,877)-0.01064 0.992 Years of education 11.55 (1.23)11.38 (2.47)-0.23164 0.821 HIV viral load (cells/mm3 [log10 transformed]) 2.55 (1.93)1.75 (2.18)-1.13861 0.26 CD4+CD3+ (cells/mm3) 455.43 (285.47)384.33 (318.05)-.68161 0.498 Table 3-2 Comparison of categorical dem ographic and health variables in particip ants who provided full and partial data. Potential control variable 2 df p value Race 4.29870.745 Marital status 2.7540.601 Presence of dysplasia 0.57810.447 HIV clinical axis .53520.765 HPV status 1.66710.197

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26Table 3-3 Predicting presence of cervical neoplasia from depressive symptoms. (Step number) predictor Wald statistic Odds ratio p Value 95% confidence interval (1) Biological variables Lower Upper HIV viral load (cells/mm3 [log10 transformed]) .476 3.1511.6090.0760.9522.722 High-risk HPV 1.634 3.0075.126.083.80832.514 CD4+CD3+ (cells/mm3) 0.000 0.0571.0000.8120.9971.004 Smoking .001 2.1031.0010.1471.0001.002 (2) Psychological variable Full BDI score 0.175 2.9771.191.0840.9971.453 N = 54. Significance of the model, 2 (5) = 16.724, p = .005. Nagelkerke R2 = .432

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27Table 3-4 Predicting presence of cervical neoplasia from cognitive/affective depressive symptoms. (Step number) Predictor Wald statistic Odds ratio p value 95% confidence interval (1) Biological variables Lower Upper HIV viral load (cells/mm3 [log10 transformed]) 0.487 3.4621.6270.0630.9742.716 High-risk HPV 1.585 3.0364.880.081.82129.026 CD4+CD3+ (cells/mm3) 0.000 0.0401.0000.8410.9971.004 Smoking .001 2.4860.1.001.1151.0001.002 (2) Psychological variable Cognitive/affective BDI score .169 2.2661.1840.1320.9501.476 N = 54. Significance of model, 2 (5) = 14.953, p = .011. Nagelkerkes R2 = .396

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28Table 3-5 Predicting presence of cervical neopl asia from somatic depressive symptoms. (Step number) Predictor Wald statistic Odds ratio p value 95% confidence interval (1) Biological variables Lower Upper HIV viral load (cells/mm3 [log10 transformed]) 0.472 2.7861.6030.0950.9212.789 High-risk HPV 1.307 1.7643.6950.184.53725.423 CD4+CD3+ (cells/mm3) 0.001 0.0021.0010.5670.9981.005 Smoking .001 1.5371.0010.2151.0001.002 (2) Psychological variable Somatic BDI score 0.791 4.1262.2060.0421.0284.733 N = 54. Significance of model, 2 (5) = 19.77 p = .001. Nagelkerkes R2 = .497

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29 CHAPTER 4 DISCUSSION Previous research has shown that depressi on and depressive symptoms are associated with negative health outcomes for individuals with HIV infection (Bur ack et al., 1993; Ickovics et al., 2001; Mayne et al., 1996; Leserman et al., 1999; Leserman et al., 2002). However, very little research has investigated the possible relationship betwee n depressive symptoms and HIVspecific pathophysiologic disease pr ocesses in women. This is a si gnificant gap in the current literature, because the relations hip between depression and speci fic HIV disease outcomes may help to explain the associations that have al ready been demonstrated between depression and more global yet highly significant outcomes, such as HIV progressi on and mortality. By identifying the specific disease processes that may underlie the previously demonstrated link between depression and HIV progr ession and mortality, specific sc reening and inte rventions can be tailored to provide the mo st effective and comprehensive treatments for HIV+ women. The current study is the first, to our know ledge, to examine the relationship between depressive symptoms and HPV-initiated cervical neoplasia, the pre-malig nant stage of cervical cancer. Cervical cancer is the most common AI DS defining malignancy in women with HIV infection (Maiman et al., 1997). The progressi on of cervical neoplasia in HIV+ women has significant clinical implications, as CIN II advanc es HIV+ women to symptomatic disease status and CIN III advances HIV+ women to a clinical AIDS diagnosis. Fortunately, cervical neoplasia is easily detectable vi a cervical cytology and histology, t hus allowing for th e initiation of treatment prior to the development of invasive cervical cancer. In addition, cervical neoplasia is initiated by HPV infection, a common, sexually-tr ansmitted virus that is controlled by the immune system and, by implication, potentially influenced by psychosocial factors that are known to influence the immunosurveillance of latent viruses.

PAGE 30

30 As expected, HR-HPV and cervi cal neoplasia were highly pr evalent in our sample. HRHPV infection was detected in 78.2% of the st udy participants, and ce rvical neoplasia was present in 81.8% of the partic ipants. Participants in our sample included women who were asymptomatic, as well as those with advanced HI V disease. Therefore, it is likely that these results can be generalized to women at a ny stage of the HIV disease continuum. Women in this study presented with wide variability in degree of depressive symptomatology, ranging from endorsing no cu rrent depressive symptoms to endorsing clinically-significant depressive symptomatology. It is possible th at women with the most severe depressive symptomatology were not adequately sampled, because they did not present for routine obstetric and gynecologic care, refused research participat ion, or did not complete full study procedures. However, in spite of the chal lenges of recruiting and retaining participants with severe depressive sympto matology, 11% of our sample endorsed symptoms suggestive of clinically significant depression. Total depressive symptomatology was only margin ally associated with cervical neoplasia in this sample of HIV+ women with HPV inf ection and there was no relationship between the cognitive/affective symptoms of depression and ce rvical neoplasia. On ly greater levels of somatic depressive symptoms were significantly associated with greater odds of cervical neoplasia, specifically increasing the odds of cervical neoplasia by approximately two-fold. This finding persisted after controlling for recent negative life event stress, a factor associated with the progression and/or persistence of cervi cal neoplasia in our prior research. This finding is consistent with research s uggesting that African Americans, who comprised the majority of our sample, may tend to ma nifest depression through primarily somatic symptoms (Das et al., 2006). In addition, it is consistent with the wealth of research

PAGE 31

31 demonstrating that women tend to present freque ntly with atypical depr ession, which includes somatic symptoms such as weight gain and prob lems with sleep (Bhatia & Bhatia, 1999). The results of the current study also appear to be consistent with some published research on somatic depression and HIV outcomes. Perkins et al. (1995) found that fatigue and insomnia were associated with dysphoric mood and major depr essive disorder in HIV+ individuals. Furthermore, one large-scale, l ongitudinal study demonstrated that somatic depressive symptoms were associated with progressi on to AIDS, progression to HIV-de mentia, and shortened survival, even after controlling for HIV medication use (Farinpour et al ., 2003). Taken together, these findings suggest that somatic depression may be a particularly important marker of depressive disorders and a correlate of important disease outcomes in HIV. Study Limitations Caution must be used when interpreting our findings given our modest sample size, undersampling of severely depressed women, an d cross-sectional desi gn, the latter of which precludes the ability to establish whether somatic depression causes cervical neoplasia or viceversa. Of note, the BDI was administered to pa rticipants after they had been notified of their Papanicolaou smear and cervical biopsy result s. This was unavoidable given that (a) study eligibility was based upon these results, and (b ) colposcopic examinations were clinically indicated, and thus it would have been unethic al to withhold cytology/histology results from participants for research purposes Although this raises some c oncern that BDI results may be confounded with CIN-related distress, it should be not ed that only par ticipants with no or grade I (mild) cervical neoplasia were eligible for the study. In addition, approximately four to six weeks typically elapsed between notification of cytology/histology results and administration of the BDI, which assessed depressive symptoma tology over the prior week only. Finally, an examination of the BDI and PEAPS-Q scores demonstrated that there was no association

PAGE 32

32 between distress related to the colp oscopy and depressive symptoms (p > .05). In concert, these factors may have restricted the degree of CIN -related distress that could be confounded with depressive symptomatology. An additional limitation of this study is that se veral participants did not have a cervical biopsy performed due the pr esence of clinical contra indications for biopsy. A cervical biopsy is necessary to establish a diagno sis of cervical neoplasia, and it is possible that cervical cytology may have underestimated the de gree of cervical neoplasia present among these participants. Future Directions Future research should utilize pros pective, longitudinal, and/or expe rimental designs to facilitate the examination of possible causal mechanisms between depressive symptoms and cervical neoplasia. For instance, somatic depression ma y increase odds of cer vical neoplasia through impaired immune functioning. Somatic depressi on may be associated with a shift in the production of cytokines from a pattern that promotes cellular immunity (Th1 cytokine production: e.g., interferon-gamma, interleukin-2, tumor necrosis factor-alpha) to one that promotes primarily humoral immunity (Th2 cy tokines production: e.g., interleukin-4, interleukin-10). This shift has been implicated in the progression of bot h HPV and HIV (Bais et al., 2006; Kedzierska & Crowe,2001). Suppressi on of cellular immunity through a decreased Th1 cytokine response may allow for tumor growth and metastasis to occu r (Rankin et al., 2003), while enhancement of a Th2 cytokine response ma y promote the survival of cancer cells through the prevention of programmed cell death ( apoptosis) (Conticello et al., 2004). Depression has also been st rongly implicated in altera tions (increases) in proinflammatory cytokines, including IL-1 IL-6, and IFN, which are capable of inducing sickness behaviors, including fa tigue, lethargy, muscle and joint pain, and anorexia (Dantzer,

PAGE 33

33 2006), symptoms that overlap greatly with soma tic depressive symptoms. In addition, recent evidence has indicated that chronic inflammati on, and thus an increase in the associated cytokines, may be involved in carcinogenic proce sses (Antoni et al., 2006; Balkwill, Charles, & Mantovani, 2005). Chronic inflammation has also been implicated speci fically as a risk factor for HPV persistence and progression to cervical cancer (Castle, 2004). Thus, bidirectional relationships between somatic depression and cytokine pr oduction, on the one hand, and cytokine production and cervical neoplasia on the other hand, may account for the present findings. In the sample used for the current study, greater somatic depr essive symptoms were associated with lower CD4+CD3+ cell counts at study entry (r = -.286, p = .036). Cognitive/affective depressive symptoms were no t associated with CD4+CD3+ cell counts. In addition, neither somatic nor cognitive/affectiv e depressive symptoms were significantly associated with HIV viral load, though ther e was a positive relationship between somatic depressive symptoms and HIV viral load that approached significance (r = .243, p = .077). While it is intriguing to consider that cy tokine production may mediate the relationship between somatic depressive symptoms and cervical neoplasia, it is equa lly possible that this relationship may be accounted for by the effects of depression on health care behaviors, such as Papanicolaou smear screening and medication adhere nce. Therefore, futu re research should be guided by a comprehensive model that would allow the testing of (a) multiple mediators of the relationship between somatic de pression and cervical neoplas ia, including both cytokine production and health behaviors, and (b) bidirect ional relationships among these variables. In summary, the findings of the present study su ggest that it may be important to assess the presence and severity of depr essive symptoms, most notably somatic depressive symptoms, among HIV+ women attending gynecol ogic and obstetric clinics. Ultimately, the identification

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34 and treatment of somatic depression among HI V+ HPV+ women may enhance health-related quality of life in part via reduc tion in risk of cervical cancer.

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35 LIST OF REFERENCES Anderson, R. N., & Smith, B. L. ( 2005). Deaths: leading causes for 2002. National Vital Statistics Report, 53 67-70. Antoni, M. H., Lutgendorf, S. K., Cole, S. W., Dhabhar, F. S., Sephton, S. E., McDonald, P. G., Stefanek, M., & Sood, A. K. (2006). The influe nce of bio-behavioural factors on tumour biology: Pathways and mechanisms. Nature Reviews Cancer, 6 240-248. Bais, A. G., Beckmann, I., Lindemans, J., Ewing, P. C., Meijer, C. J. L. M., Snijders, P. J. F., & Helmerhorst, T. J. M. (2006). A shift to a pe ripheral Th2-type cytoki ne pattern during the carcinogenesis of cervical cancer beco mes manifest in CIN III lesions. Journal of Clinical Pathology, 58, 1096-1100. Balkwill, F., Charles, K. A., & Mantovani, A. (2005). Smoldering and polarized inflammation in the initiation and promoti on of malignant disease. Cancer Cell, 7 211-217. Beck, A. T. (1967). Depression: Clinical, experimental, and th eoretical aspects. New York: Hoeber. Beck, A. T., Ward, C. H., Mendelson, M., Moc k, J., & Erbaugh, J. (1961). An inventory for measuring depression. Archives of General Psychiatry, 4, 561-571. Bennetts, A., Irwig, L., Oldenburg, B., Simpson, J. M., Mock, P., Boyes, A., Adams, K., Weisberg, E., & Shelley, J. (1995). PEA PS-Q: A questionnaire to measure the psychosocial effects of having an abnormal pap smear. Journal of Clinical Epidemiology, 48, 1235-1243. Bhatia, S. C., & Bhatia, S. K. (1999) Depr ession in women: Diagnostic and treatment considerations. American Family Physician, 60, 225-234. Blaney, N. T., Fernandez, M. I., Ethier, K. A., Wilson, T. E., Walter, E., & Koenig, L. J. (2004). Psychosocial and behavioral correlates of depression among HIV-infected pregnant women. AIDS Patient Care and STDS 18, 405-415. Burack, J. H., Barrett, D. C., Stall, R. D., Ch esney, M. A., Ekstrand, M. L., & Coates, T. J. (1993). Depressive symptoms and CD4 lym phocyte decline among HIV-infected men. The Journal of the American Medical Association, 270, 2568-2573. Byrnes, D. M., Antoni, M. H., Goodkin, K., Efantis -Potter, J., Asthana, D ., Simon, T., Munajj, J., Ironson, G., & Fletcher, M. A. (1998). Stress ful events, pessimism, natural killer cell cytotoxicity, and cytotoxic/suppressor T cells in HIV+ black women at risk for cervical cancer. Psychosomatic Medicine, 60 714-722. Castellon, S. A., Hinkin, C. H., Wood, S., & Yarema, K. T. (1 998). Apathy, depression, and cognitive performance in HIV-1 infection. The Journal of Neuropsychiatry and Clinical Neurosciences, 10, 320-329.

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37 Hocke C., Leroy V., Morlat P., Rivel J., Duluc M. C., Boulogne N., Tandonnet, B., Dupon, M., Brun, J. L., & Dabis, F. (1998). Cervical dysplasia and human i mmunodeficiency virus infection in women: Prevalen ce and associated factors. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 81 69-76. Ickovics, J. R., Hamburger, M. E., Vlahov, D., Schoenbaum, E. E., Schuman, P., Boland, R. J., & Moore, J, HIV Epidemiology Resear ch Study Group. (2001). Mortality, CD4 cell count decline, and depressive symptoms among HIV-seropositive women: Longitudinal analysis from the HIV Epidemiology Research Study. The Journal of the American Medical Association, 285, 1466-1474. Janeway, C. A., Travers, P., Walpor t, M., & Shlomchik, M. J. (2001). Immunobiology (5th ed.). New York: Garland Publishing. Joint United Nations Prog ramme on HIV/AIDS. (2004). 2004 report on the global AIDS epidemic: 4th global report. Geneva: Switzerland. Jones, D. J., Beach, S. R., & Forehand, R. ( 2001). HIV infection and depressive symptoms: an Investigation of African American single mothers. AIDS Care, 13 343-50. Judd, F., Komiti, A., Chua, P., Mijch, A., Hoy, J ., & Grech, P. (2005). Nature of depression in patients with HIV/AIDS. The Australian and New Zeland Journal of Psychiatry, 39, 826832. Kedzierska, K., & Crowe, S. M. (2001). Cyt okines and HIV-1: Interactions and clinical implications. Antiviral Chemistry & Chemotherapy, 12, 133-150. Kendler, K. S., Karkowski, L. M., & Prescott C. A. (1999). Causal relationship between stressful life events and the onset of major depression. American Journal of Psychiatry,156, 837-841. Laperriere, A., Ironson, G. H., Antoni, M. H., Pomm, H., Jone s, D., & Ishii, M. (2005). Decreased depression up to one year follo wing CBSM+ intervention in depressed women with AIDS: the smart/EST womens project. Journal of Health Psychology, 10, 223-231. Leserman, J., Jackson, E. D., Petitto, J. M., Golden, R. N., Silva, S. G., Perkins, D. O., Cai, J., Folds, J. D., & Evans, D. L. (1999). Progression to AIDS: The effects of stress, depressive symptoms and social support. Psychosomatic Medicine, 61, 397-406. Leserman, J., Petitto, J. M., Gu, H., Gaynes, B. N., Barroso, J., Golden, R. N., Perkins, D. O., Folds, J. D., & Evans, D. L. (2002). Progres sion to AIDS, a clinical AIDS condition, and mortality: Psychosocial a nd physiological predictors. Psychological Medicine, 32, 10591073.

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38 Lyketsos, C. G., Hoover, D. R., Guccione, M., Se nterfitt, W., Dew, M. A., Wesch, J., VanRaden, M. J., Treisman, G. J., & Morgenstern, H. (199 3). Depressive symptoms as predictors of medical outcomes in HIV infec tion. Multicenter AIDS Cohort Study. Journal of the American Medical Association, 270, 2563-2567. Maiman, M., Fruchter, R., Clark, M., Arrastia, C., Matthews, R., & Gates, E. J. (1997). Cervical cancer as an AIDS-defining illness. Obstetrics and Gynecology, 89, 76-80. Mayne, T. J., Vittinghoff, E., Chesney, M. A., Barrett, D. C. & Coates, T. J. (1996). Depressive affect and survival among gay and bisexual men infected with HIV. Archives of Internal Medicine, 156, 2233-2238. Morrison, M. F., Petitto, J. M., Ten Have, T., Ge ttes, D. R., Chiappini, M. S., Weber, A. L., Brinker Spence, P., Bauer, R. M., Douglas, S. D., & Evans, D. L. (2002). Depressive and anxiety disorders in women with HIV infection. American Journal of Psychiatry, 159, 789-796. Munoz, N., Bosch, F. X., de Sanjose, S., Herrero, R., Castellsaque, X., Shah, K. V., Snijders, P. J., & Meijer, C. J. (2003). Epidemiologic cl assification of human papillomavirus types associated with cervical cancer. New England Journal of Medicine, 348 518-27. Nadler, J. P. (2006). Pathophysiology of HIV infec tion. In J. Beal, J. Orrick, K. Alfonso, & M Rathore (Eds.), HIV/AIDS Primary Care Guide (17-30). Carmarthen, UK: Crown House Publishing. National Center for Health Statistics. (2005). Health, United States, 2005: With chartbook on trends in the health of Americans Hyattsville, Maryland. Pereira, D. B., Antoni, M. H., Danielson, A., S imon, T., Efantis-Potter, J ., Carver, C. S., Duran, R. E., Ironson, G., Klimas, N., Fletcher, M. A., & OSullivan, M. J. (2003a). Stress as a predictor of symptomatic genital herpes virus recurrence in women with human immunodeficiency virus. Journal of Psychosomatic Research, 54, 237-44. Pereira, D. B., Antoni, M. H., Danielson, A., S imon, T., Efantis-Potter, J., Carver, C.S., Duran, R. E., Ironson, G., Klimas, N., & OSullivan, M. J. (2003b). Life Stress and cervical squamous intraepithelial lesions in wome n with human papillomavirus and human immunodeficiency virus. Psychosomatic Medicine, 65 427-434. Perkins, D. O., Leserman, J., Stern, R. A., Baum, S. F., Liao, D., Golden, R. N., & Evans, D. L. (1995). Somatic symptoms and HIV infection: Relationship to depressive symptoms and indicators of HIV disease. American Journal of Psychiatry, 152, 1776-1781. Phelps, R. M., Smith, D. K., Heilig, C. M., Gar dner, L. I., Carpenter, C. C., Klein, R. S., Jamieson, D. J., Vlahov, D., Schuman, P., & Holm berg, S. D. (2001). Cancer incidence in women with or at risk for HIV. International Journal of Cancer 94 753-757.

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39 Pyszczynski, T., Holt, K., & Greenberg, J. ( 1987). Depression, self-f ocused attention, and expectancies for positive and negative future life events for self and others. Journal of Personality and Social Psychology, 52, 994-1001. Rabkin, J. G., Williams, J., Remien, R. H., Goetz, R., Kertzner, R., & Gorman, J. M. (1991). Depression, distress, lymphocyte subsets, a nd human immunodeficiency virus symptoms on two occasions in HIV-positive homosexual men. Archives of General Psychiatry, 48, 111-119 Rankin, E. B., Yu, D., Jiang, J., Shen, H., Pearce, E. J., Goldschmidt, M. H., Levy, D. E., Golovkina, T. V., Hunter, C. A., & Thomas-T ikhonenko, A. (2003). An essential role of Th1 responses and interferon gamma in inf ection-mediated suppression of neoplastic growth. Cancer Biology & Therapy, 2 687-693 Sahs, J. A., Goetz, R., Reddy, M., Rabkin, J. G., Williams, J. B., Kertzner, R., & Gorman, J. M. (1994). Psychological distress and natural kille r cells in gay men with and without HIV infection. American Journal of Psychiatry, 151, 1479-1484. Sarason, I. G., Johnson, J. H., & Siegel J. M. (1978). Assessing the im pact of life change: development of the Life Experiences Survery. Journal of Consulting and Clinical Psychology, 46, 932-946. Scott, M., Stites, D. P., & Moscicki, A. B. (1999). Th1 cytokine patt erns in cervical human papillomavirus infection. Clinical and Diagnostic Laboratory Immunology, 6, 751-5. Tiersma, E. S. M., van der Lee, M. L., Garssen, B., Peters, A. A. W., Visser, A. P., Fleuren, G. J., van Leeuwen, K. M., le Cessie, S., & Goodkin, K. (2005). Psychosocial factors and the course of cervical intra-epith elial neoplasia: A prospective study. Gynecologic Oncology, 97, 879-886. Tiersma, E. S., van der Lee, M. L., Peters, A. A., Visser, A. P., Jan Fleuren, G., Garssen, B., van Leeuwen, K. M., le Cessie, S., & Goodkin, K. (2004). Psychosocial factors and the grade of cervical intra-epithelial neopl asia: A semi-prospective study. Gynecologic Oncology, 92, 603-10. Vedhara, K., Schifitoo, G., & McDermott, M. (1999). Disease progression in HIV-positive women with moderate to severe immunosuppr ession: the role of depression. Dana Consortium on Therapy for HIV Dementia and Related Cognitive Disorders. Behavioral Medicine, 25, 43-47. U.S. Census Bureau; Census 2000, Profile of General Demographic Characteristics (DP1); generated by Stacy Dodd; using American Factfinder; http://fact finder.census.gov/; (26 April 2006).

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40 Weiser, S. D., Riley, E. D., Ragland, K., Hamme r, G., Clark, R., & Bangsberg, D. R. (2006). Brief report: Factors associated with de pression among homeless and marginally housed HIV-infected men in San Francisco. Journal of General Internal Medicine, 21, 61-64. Weissman, M. M., & Oflson, M. (1995). Depressi on in women: Implications for health care research. Science, 269, 799-801.

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41 BIOGRAPHICAL SKETCH Stacy Dodd graduated with honors from the Univ ersity of Michigan in 2005, receiving a Bachelor of Arts degree in Psychology. During her time at th e University of Michigan, she worked as a research assistant for the Familie s and Communities Together Coalition on a study investigating the effects of a group intervention for women a nd children who had experienced domestic violence. She also completed an unde rgraduate honors thesis on the worries of childhood cancer patients and their mothers and the ab ilities of each to predict the worries of the other. Stacy began attending graduate school at the University of Florida in the department of Clinical and Health Psychology in August 2005. She is focusing her research on psychooncology, psychneuroimmunology, and womens health. She is currently pursuing her Ph.D. in Clinical Psychology.


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Title: Depressive Symptoms and Cervical Neoplasia in HIV+ Women with Human Papillomavirus Infection
Physical Description: Mixed Material
Copyright Date: 2008

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DEPRESSIVE SYMPTOMS AND CERVICAL NEOPLASIA IN HIV+ WOMEN WITH
HUMAN PAPILLOMAVIRUS INFECTION




















By

STACY MARIE DODD


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA

2007
































O 2007 Stacy Marie Dodd





































To Jeriann Dodd









ACKNOWLEDGMENTS

First, I thank Dr. Deidre Pereira for her mentorship, guidance, and support throughout the

many phases of this proj ect. Her depth of knowledge, insightful advice, and passion for research

has been instrumental in the completion of this work. I thank Dr. Michael Antoni, the principle

investigator on this study, for allowing me to participate in this research. Additionally, I extend

my appreciation to Ms. Sally Jensen, who has served as an excellent role model and provided

guidance throughout this process. I would like to thank Ms. Ilona Buscher, Dr. Michele Peake,

Ms. Trudi Simon, Dr. Mary Ann Fletcher, and Dr. Kevin Maher at the University of Miami for

their involvement in this study. I also acknowledge the members of my committee, Dr. Samuel

Sears, Dr. Dawn Bowers, and Dr. Stephen Boggs.

I would like to thank my family, and specifically my parents, for their endless support.

Without my mother and father none of this would have been possible. I thank my mother for

being my inspiration for pursuing research in this field. I would also like to thank my friends

and classmates for their guidance and support as well as camaraderie throughout this process.

I extend my great appreciation for all of the women who participated in this research. I

wish them the best.












TABLE OF CONTENTS



ACKNOWLEDGMENTS .............. ...............4.....


LIST OF TABLES ................ ...............7............ ....


AB S TRAC T ......_ ................. ............_........8


CHAPTER


1 INTRODUCTION ................. ...............10.......... ......


Epidemiology of HIV ............. ..... __ ...............10..
Pathophysiology ofHIV/AIDS............... ...............1
HIV/AIDS Classification............... .............1
HIV and Human Papillomavirus .............. ...............12....
Psychoneuroimmunology and CIN................ ...............13..
Depression and HIV .............. ...............14....
Current Study ................. ...............15.......... ......


2 METHODS ................. ...............17.......... .....


Design ................. ...............17.................
Participants .............. ...............17....
Proc edure s ................ ...............18........... ....
Screening Visit .............. ...............18....
Psychosocial Interview............... ...............1
Statistical Procedures............... ...............1


3 RE SULT S .............. ...............21....


Demographics ................. ...............21.................
Health Behaviors .............. ...............21....
Health Status ................. ...............22.................

Depressive Symptoms ............... ......... .............. .......2
Relations between Depressive Symptoms and HIV-Related Immunity ............... .................22
Relations between Biobehavioral Variables and Cervical Neoplasia............... ................2
Relations between Depressive Symptomatology and Cervical Neoplasia .............................23


4 DI SCUS SSION .........__. ....._..... ...............29....


Study Limitations. ........._.._.. ...._... ...............3 1....
Future Directions .............. ...............32....











LIST OF REFERENCES ................. ...............35................

BIOGRAPHICAL SKETCH .............. ...............41....


































































6










LIST OF TABLES


Table page

1-1 CDC classification ofHIV/AIDS. ............. ...............16.....

3-1 Comparison of continuous demographic and health variables in participants who
provided full and partial data. .............. ...............25....

3-2 Comparison of categorical demographic and health variables in participants who
provided full and partial data. .............. ...............25....

3-3 Predicting presence of cervical neoplasia from depressive symptoms. .............................26

3-4 Predicting presence of cervical neoplasia from cognitive/affective depressive
sym ptom s. ............. ...............27.....

3-5 Predicting presence of cervical neoplasia from somatic depressive symptoms. ...............28









Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science

DEPRESSIVE SYMPTOMS AND CERVICAL NEOPLASIA IN HIV+ WOMEN WITH
HUMAN PAPILLOMAVIRUS INFECTION

By

Stacy Marie Dodd

May 2007

Chair: Deidre Pereira
Major: Psychology

Prior work has related elevated life stress to greater risk of cervical neoplasia in women co-

infected with human immunodeficiency virus (HIV) and human papillomavirus (HPV). This

study investigated associations between depressive symptoms (independent of life stress and

other possible confounders) and cervical neoplasia in women with HIV and HPV infection.

Participants for this study were 54 HIV+HPV+ women; most were African American.

Participants underwent a colposcopy, HPV screening, Papanicolaou smear, and cervical biopsy

to determine study eligibility. Eligible participants then completed the Beck Depression

Inventory (BDI). Scores on the BDI were used as a whole and were also divided into

cognitive/affective symptoms and somatic symptoms. Hierarchical logistic regression analysis

revealed that women who reported more depressive symptoms had marginally greater odds of

presenting with cervical neoplasia, OR = 1.32, p = .062. While cognitive and affective

depressive symptoms were not significantly associated with greater odds of presenting with

cervical neoplasia, women who reported more somatic depressive symptoms had greater odds of

presenting with cervical neoplasia, OR = 2.29 p = .022, even after controlling for biobehavioral

risk factors for cervical neoplasia (HIV viral load and high-risk HPV) and recent negative life

events. Thus, women who reported more somatic depressive symptoms had greater odds of










presenting with cervical neoplasia. These findings may suggest that screening HIV+ women for

somatic depression may help identify those at risk for cervical neoplasia. In addition, these

findings suggest that future research on depression in medical populations should not ignore

somatic depressive symptoms, as they may have important implications for health outcomes.









CHAPTER 1
INTRODUCTION

Epidemiology of HIV

Human immunodeficiency virus (HIV) is the virus that causes acquired

immunodeficiency syndrome (AIDS). HIV and AIDS are serious global health threats. In 2003,

an estimated 4.8 million people worldwide became newly infected with HIV. Approximately

37.8 million people are currently living with HIV. Over 20 million have died from the disease

since the epidemic began in 1981; 2.9 million died in 2003 alone (Joint United Nations

Programme on HIV/AIDS [UNAIDS], 2004). In the United States, 43,171 new AIDS cases

were reported to the Center for Disease Control and Prevention (CDC) in 2003. Of these, 21,304

(49.3%) cases were diagnosed in African Americans compared to 12,222 (28.3%) cases

diagnosed in Caucasians. AIDS-related mortality is also higher among African Americans than

Caucasians. Death rates associated with AIDS are nearly 8 times higher in African American

men than Caucasian men. For women the disparity was even larger: death rates for African

American women due to AIDS are nearly 13 times higher than those for Caucasian women

(National Center for Health Statistics, 2005). In 2002, HIV/AIDS was the leading cause of death

in African American women between the ages of 25 and 34 (Anderson & Smith, 2005). These

discrepancies are even more pronounced since African Americans constitute only 12.3% of the

U.S. population (U.S. Census Bureau data for 2000, 2006). Although HIV and AIDS are serious

health threats for all Americans, the virus and disease have a disproportionately large impact on

the African American community.

Pathophysiology of HIV/AIDS

Infection with HIV occurs through mucosal contact with bodily fluids infected with the

virus. This occurs through sexual intercourse or the sharing of contaminated needles. In the past,









HIV infection occurred following medical transfusion of infected blood products; this has

become rare subsequent to blood screening procedures to identify infected blood. Approximately

2-6 weeks following initial infection, most (but not all) individuals experience an influenza-like

illness corresponding with the initiation of HIV-specific cellular immune responses (Nadler,

2006). During this time, cytotoxic T-cells (CD8 T-cells) are activated and work to kill HIV

infected cells and HIV antibody production occurs (Janeway, Travers, Walport & Shlomchik,

2001).

After the primary infection stage, HIV enters the second stage of infection, often referred

to as the asymptomatic stage. Though individuals in this stage generally do not express any

clinical symptoms, the virus continues to replicate and CD4 T-cell counts continue to decline

(Nadler, 2006). One of the primary factors influencing the amount of time an individual remains

in the asymptomatic stage is the initial effectiveness of the immune response to contain the

infection. The HIV viral load that is established subsequent to initial infection remains fairly

stable over several years, and those with the highest viral loads generally have faster progressing

HIV infection (Nadler, 2006). For most individuals, this second stage of HIV infection

eventually progresses to clinical AIDS, which is characterized by low CD4 cell counts and/or the

development of an AIDS-defining illness, as described below.

HIV/AIDS Classification

In 1993, the CDC revised the classification system for HIV/AIDS. According to the

revisions, HIV/AIDS is classified using three ranges of CD4 cell counts and three clinical

categories.

The three ranges of CD4 cell counts used to classify HIV infection are 500 cells/CIL or

greater (Category 1), 200-499 cells/CIL (Category 2), and less than 200 cells/CIL (Category 3).

Individuals in Category 3 are classified as having developed AIDS, regardless of whether they









have developed an AIDS defining condition. Category determinations are made based upon the

lowest accurate CD4 cell count for that individual, which is not necessarily the most recent cell

count obtained (CDC, 1992).

The three clinical categories of HIV/AIDS are Category A, B, and C. An individual is

categorized as being in Category A, or asymptomatic HIV, if they have never experienced a

symptomatic AIDS condition or an AIDS-defining illness (described below). Category B, or

symptomatic HIV, is assigned to individuals who have experienced a symptomatic condition

occurring in an HIV infected individual that is either attributed to the HIV infection or indicates

a deficit in cell-mediated immunity, or conditions that have a clinical course that is complicated

by the HIV infection. These do not include conditions designated as AIDS-defining illnesses.

Category C, or clinical AIDS, is reached when an individual experiences an AIDS-defining

illness as defined by the CDC. Classifieation of the clinical categories are based upon the history

of HIV progression, thus once an individual meets criteria for a category they cannot move back

into a previous category, even if the symptoms or illness placing them in the category is resolved

(CDC, 1992).

Based upon the three CD4 cell count categories and the three clinical categories, there are

nine mutually exclusive categories for the staging of HIV/AIDS, ranging from Al-C3 (Table 1-

2). Categories A3, B3, C3, C1, and C2 confer a diagnosis of AIDS.

HIV and Human Papillomavirus

HIV infection may have a different course in women compared to men. Specifically,

several opportunistic illnesses are more common, harder to treat, or occur exclusively in women

with HIV as compared to their male counterparts. Examples include disorders of the upper

genital tract, such as pelvic inflammatory disease, as well as disorders of the lower genital tract,

such as cervical intraepithelial neoplasia (CINT) (CDC, 1992). CIN is the pre-malignant phase of









cervical cancer that is initiated and promoted to cervical cancer by oncogenic Human

Papillomavirus (HPV) infection, including HPV 16 and 18 infections. HPV is one of the most

common sexually transmitted infections in the United States. Among immunocompetent women

with HPV infection, adequate cellular immune responses, most notably T helper type 1 (Thl)

cell immune responses (Scott, Stites, & Moscicki, 1999), will survey the virus before it promotes

the pre-malignant or malignant transformation of cells (Munoz et al., 2003). However, HPV

infected women with suppressed cellular immune responses, such as women with

immunodeficiency due to HIV infection, are not able to mount an adequate immune defense

against HPV, resulting in persistent and severe HPV infection and risk for malignant

transformation of cells. Additional risk factors for CIN and cervical cancer among women with

HIV include degree of immunosuppression (low T helper/inducer lymphocyte [CD4+CD3+] cell

counts) (Phelps et al., 2001; Davis et al., 2001), tobacco smoking (Hocke et al., 1998), and

uncontrolled HIV viral load (Davis et al., 2001).

Psychoneuroimmunology and CIN

Pyschoneuroimmunology (PNI) is the investigation of the relations among psychosocial

variables, neuroendocrine and immunologic functioning, and health outcomes. Research

investigating psychosocial variables and the presence and/or persistence of CIN has yielded

inconsistent results. Previous research has shown that poorer psychological well-being (greater

pessimistic attitude, greater negative life event stress) is associated with lower cell-mediated and

natural immunity (Byrnes et al., 1998), greater number of genital herpes recurrences (Pereira et

al., 2003b), and greater odds of progression and/or persistence of cervical neoplasia (Pereira et

al., 2003a) in women with HIV and HPV infections. In contrast, other researchers have reported

no associations between CIN progression or regression with negative life events, lack of social

support, or coping style (Tiersma et al., 2005; Tiersma et al., 2004). However, no research to









date has explored whether other common and treatable psychological conditions, such as

depression, are associated with cervical neoplasia in women with HIV and HPV infections.

Depression and HIV

The relationship between depression and health status in HIV+ women is particularly

important to examine for several reasons. Depressive symptoms and disorders are common

among individuals with HIV infection. Studies have shown that nearly half of individuals with

HIV infection meet diagnostic criteria for depression (Chandra et al., 1998). HIV+ women may

be at particularly high risk of experiencing depressive symptoms. Studies have shown that

women in the general population experience maj or depression twice as often as men (Weissman

& Off son, 1995), and women infected with HIV experience maj or depression significantly more

often than healthy women (Morrison et al., 2002). In addition, HIV+ women experience

depression at rates twice that of HIV+ men (Evans et al., 2002). Notably, depressive symptoms

in HIV+ individuals are associated with more rapid decline of CD4+CD3+ cell counts (Rabkin et

al., 1991; Lyketsos et al., 1993; Sahs et al., 1994; Vedhara, Schifitoo, & McDermott, 1999;

Burack et al., 1993; Ickovic et al., 2001), decreased natural killer (NK) cell activity, increased

HIV viral load, and greater risk of HIV related mortality (Burack et al., 1993; Ickovics et al.,

2001; Mayne et al., 1996; Leserman et al., 1999). Depressive symptoms are also associated with

faster development of any AIDS defining condition (Leserman et al., 2002).

In spite of this research, no research to our knowledge has investigated the possible

relationship between depressive symptoms and cervical neoplasia, a female-specific HIV

associated opportunistic illness. This relationship is of particular interest, because susceptibility

to depression is elevated among women experiencing high life stress (Kendler, Karkowski, &

Prescott, 1999) and individuals who are dispositionally pessimistic (Beck, 1967; Pyszcynski,

Holt, & Greenberg, 1987), two psychosocial factors previously associated with lowered









immunity and progression and/or persistence of cervical neoplasia in HIV+ HPV+ women

(Byrnes et al., 1998; Pereira et al., 2003).

Current Study

The purpose of the current study was to determine whether recent depressive symptoms

were associated with the presence of cervical neoplasia in a sample of primarily Black/African

American women with HIV and HPV infections recruited for a trial examining the effect of a

cognitive behavioral stress management (CBSM) intervention on health (e.g., cervical neoplasia)

and quality of life outcomes. It was specifically hypothesized that women with greater recent

depressive symptomatology would have greater odds of cervical neoplasia at study entry. Given

that HIV-related symptoms and medication side effects may be confounded with somatic

symptoms of depression (Blaney et al., 2004; Jones, Beach, & Forehand, 2001), we also

examined whether greater cognitive/affective symptoms of depression, specifically, were

associated with greater odds of cervical neoplasia.









Table 1-1 CDC classification ofHIV/AIDS.
Clinical Categories


CD4 Cell
Categories


B (Symptomatic
A (Asymptomatic HIV) HIV)


C (AIDS
defining illness)
Cl
C2
C3


1 500 or greater cells/ CIL Al Bl
2 200-499 cells/CIL A2 B2
3 less than 200 cells/CIL A3 B3
Note: Categories A3, B3, C3, Cl and C2 receive a diagnosis of AIDS.









CHAPTER 2
METHOD S

Design

The current study utilized a cross-sectional design. Fifty-four women co-infected with HIV

and HPV underwent a colposcopy, HPV testing and subtyping, a peripheral venous blood draw,

urine collection, and a 60-90 minute psychosocial interview assessing mood and health

behaviors. Statistical analyses examined the relationships between depressive symptomatology

and the presence or absence of cervical neoplasia at study entry, while controlling for known

biobehavioral risk factors for cervical neoplasia.

Participants

Participants for this study were recruited as part of a longitudinal National Cancer

Institute (NCI) funded study investigating the effects of a cognitive-behavioral stress

management (CBSM) intervention on the health and quality of life of women with HIV at risk

for cervical cancer (PI: Michael H. Antoni, Ph.D., 5 P50 CA 084944-05). Inclusion criteria

were: (a) HIV+ women ages 18 to 60 years old, (b) history of at least 2 Papanicolaou smears

indicating low grade squamous intraepithelial lesions (LSIL) or 2 cervical biopsies indicating

CINT I in the 2 years prior to study entry, and (c) fluency in spoken English. Exclusion criteria

were: (a) 2 or more negative Papanicolaou smears in the 2 years prior to study entry, (b) any

history of high grade SIL (HSIL) or any history of CIN II, CIN III, or invasive cervical cancer,

(c) any diagnostic or treatment procedures for CIN in the 6 months prior to study entry, (d) life

expectancy < 12 months as determined by the study's research nurse, and (e) current maj or,

severe psychiatric illnesses that would interfere with the ability to provide valid psychosocial

assessment data (e.g., suicidality, psychoticism, HIV dementia).









Procedures

Participants for this study were recruited through Special Immunology Clinics at the

University of Miami/Jackson Memorial Hospitals. Patients at the Special Immunology Clinics

were initially screened based on medical record data to determine whether they met basic

eligibility requirements. If a patient passed the preliminary eligibility screening, a researcher

approached her during her visit to the clinic and explained the study. Patients that were

interested in participating in the study were scheduled to come in for a formal screening

appointment.

Screening Visit

At the formal screening appointment, the study was explained in more detail and

informed consent was completed. In addition, the participant provided information on her

gynecologic history, underwent a psychological screening, was provided an educational module

regarding colposcopies, and a colposcopy was performed. The colposcopy was comprised of a

Papanicolaou smear, colposcopic-guided cervical biopsy, and cervical swab for the detection and

subtyping of HPV infection. Based on the results of the colposcopy, participants were classified

as being positive or negative for cervical neoplasia at study entry. Hybrid Capture (HC) II assay

(Digene Corporation, Gaithersburg, MD) was used to classify HPV subtypes as intermediate to

high risk HPV (oncogenic subtypes) or low risk HPV subtypes. Immediately following the

colposcopy, participants were administered the Psychosocial Effects of Abnormal Pap Smears

Questionnaire (PEAPS-Q Bennetts et al., 1995) to measure distress related to the colposcopy.

Participants also underwent a peripheral venous blood draw in order to measure CD4+CD3+ cell

counts and plasma HIV viral load. At the end of this visit, participants were given urine

collection materials and instructions on collecting urine before their next visit. They were then









contacted approximately one week later with the results of the screening and to inform them of

whether or not they were ultimately eligible to participate in the study.

Psychosocial Interview

If the participant was eligible for study participation after the formal screening, she was

scheduled for another visit. At this visit, participants completed a psychosocial assessment

interview. This interview included the Beck Depression Inventory (BDI Beck, Ward,

Mendelson, Mock & Erbaugh, 1961) and a general demographic questionnaire, among other

psychosocial measures. The BDI is a 21-item self-report questionnaire that measures symptoms

of depression. The BDI has been used extensively in previous research investigating depressive

symptoms in HIV+ populations (Castellon, Hinkin, Wood & Yarema, 1998; Ferrando, Rabkin,

de Moore & Rabkin, 1999; Judd et al., 2005; Laperriere et al., 2005; Weiser et al., 2006).

Questions on the BDI assess both cognitive and affective (e.g., sadness, hopelessness) as well as

somatic (e.g. fatigue, weight change) depressive symptoms. Thus it is possible to create scale

scores from the BDI, which measure an individual's levels of cognitive/affective and somatic

depressive symptoms independently.

Statistical Procedures

Results presented in this paper are based upon cross-sectional psychosocial (i.e., BDI

scores) and biological (i.e., cervical neoplasia) data. We started by examining relations between

potential demographic and biobehavioral control variables and cervical neoplasia in this sample.

We then examined the relationship between recent depressive symptoms and the presence of

cervical neoplasia in women with HIV and HPV infection using hierarchical logistic regression.

Regression equations contained two blocks of predictor variables: the first block consisted of

traditional, well-established risk factors for cervical neoplasia in HIV+ women (CD4+CD3+ cell

count, HIV viral load, HR-HPV infection, and tobacco smoking) (Davis et al., 2001; Hocke et









al., 1998; Phelps et al., 2001), and the second block consisted of our psychosocial predictor of

interest scores on the BDI. Two hierarchical logistic regression equations were analyzed. The

first equation contained scores from all 21 items of the BDI. The second equation contained

scores from only the cognitive/affective items of the BDI (i.e., BDI items 1 15). The criterion

in both equations was presence ("1") or absence ("O") of cervical neoplasia by histology

(cervical biopsy) at study entry. If a cervical biopsy was clinically contraindicated for a

particular participant, the presence or absence of squamous intraepithelial lesions (SIL) by

cervical cytology (Papanicolaou smear) at study entry was used.









CHAPTER 3
RESULTS

Demographics

Sixty-six women met study criteria and were enrolled in this study. The results reported

here are based on 54 participants who provided full psychosocial, colposcopic, and immune data.

Results of t-tests and chi-square analyses revealed that participants who provided complete data

did not differ significantly (p > .05) from those who had incomplete data in age, yearly income,

years of education, ethnicity, marital status, presence of neoplasia, presence of high-risk HPV,

HIV stage, or CD4+CD3+ cells/mm3. (Tables 3-1 & 3-2).

The 54 participants who provided full data ranged in age from 18-45 years (M = 30 years,

SD = 8.5 years). The majority of the women were non-Hispanic Black/African American

(85.2%), with the remainder of the sample being comprised of Hispanic Caucasian (9.3%), non-

Hispanic Caucasian (3.7%), and other (1.9%). The women had an average yearly income of

$11,601 (S = $8,089), and averaged 11.6 years of education (SD = 1.23 years). The majority

of women in the study (55.6%) were single/never married. Of the remaining 44.4%, 20.4% were

married or in an equivalent relationship and 24% were separated, divorced, or widowed.

Health Behaviors

Seventy-two percent of the women who participated in this study were taking highly

active anti-retroviral therapy (HAART) at the time of study entry. Self-reported adherence to

HAART was significantly negatively correlated with HIV viral load, r = -.413, p = .011. Nearly

60% of the participants reported never having smoked. Of the remaining women who did report

a history of smoking (N = 22), pack-years of smoking ranged from 6 5,110 (M = 1,904, SD =

1,880).









Health Status

Colposcopic-guided cervical biopsy revealed that 44 women (81.5%) presented with

cervical neoplasia at study entry, while 10 women (18.5%) did not show evidence of cervical

neoplasia. HPV screening and typing revealed that 42 women (77.7%) tested positive for

intermediate or HR-HPV types.

Twenty-three women (42.6%) had Category A (asymptomatic) disease at study entry.

Thirteen women (24. 1%) had Category B (symptomatic) disease, and 17 women (31.5%) had

Category C (clinical AIDS) disease. The mean CD4+CD3+ cells/mm3 was 455.43 (SD =

285.47). Eight women (14.8%) had CD4+CD3+ cell counts below 200 cells/mm3, 27 women

(50%) had cell counts between 200 and 500 cells/mm3, and 19 women (35.2%) had cell counts

above 500 cells/mm3

Depressive Symptoms

Possible scores on the BDI range from 0-63, with higher scores indicating more depressive

symptoms reported. The women in this study scored between 0-44 on the full BDI, with a mean

of 8.6 (jS = 9.81). Previous research with HIV populations has utilized a BDI cutoff score of 10

to indicate depression (Laperriere et al., 2005), thus the average score for women in this study

was below depression cutoffs on the BDI. Twenty-one women (39%) in the study obtained BDI

scores of 10 or greater.

Relations between Depressive Symptoms and HIV-Related Immunity

The results of correlational analyses demonstrated that neither total BDI scores nor

cognitive/affective BDI scores were correlated with CD4+CD3+ cell counts; however, women

with greater somatic BDI scores had significantly lower CD4+CD3+cell counts, r = -.286, p =

.036. BDI scores (total, cognitive/affective, and somatic) and HIV viral load were not correlated

(P's > .05).









Relations between Biobehavioral Variables and Cervical Neoplasia

Correlational and chi-squared analyses were conducted to determine whether variables that

have been shown to be risk factors of cervical neoplasia in HIV+ women (HIV viral load,

presence of HR-HPV subtypes, CD4+CD3+ cell counts, and tobacco smoking) were related to

cervical neoplasia in this sample. HIV viral load (r = .30, p = .027) and presence of HR-HPV

subtypes (E [1] = 5.48, p = .019) were significantly related to the presence of neoplasia. Despite

the fact that CD4+CD3+ cell counts and tobacco smoking were not significantly related to

neoplasia, all four potential risk factors were entered as control variables into Block 1 of the

regression equations as a conservative measure based on their strong associations with incidence

of neoplasia in previous research.

Relations between Depressive Symptomatology and Cervical Neoplasia

Using scores from the entire BDI as the predictor of interest, a marginally significant

relationship emerged between greater depressive symptomatology and greater odds of cervical

neo lasia, OR = 1.19, 95% CI = .0.98 1.45, = .084. The overall model was si nificant, 2 5

= 16.72, 12 = 0.005 (Table 3-3). Subsequently, the relationship between only the

cognitive/affective items of the BDI, specifically, and cervical neoplasia was examined.

Contrary to our hypothesis, there was no significant relationship between cognitive/affective

s mtoms of d pression and the odds of cervical neo lasia, OR = 1.18, 95% CI = 0.95 1.48,

= 0.181 (Table 3-4).

Given that there was (a) a marginally significant relationship between scores on the entire

BDI and cervical neoplasia and (b) no significant relationship between the cognitive/affective

scores and neoplasia, we explored the possibility that scores on the somatic items of the BDI

(BDI items 16-21) were related to greater odds of cervical neoplasia. Hierarchical logistic

regression analysis revealed that women who reported higher levels of recent somatic depressive










symptomatology had over two-fold greater odds of cervical neoplasia, OR = 2.21, 95% CI = 1.03

- 4.73, p = 0.042. The overall model was significant, 2C (5) = 19.77 p = 0.001 (Table 3-5). In

order to ensure that the relationship between recent somatic depressive symptoms and cervical

neoplasia was independent of life stress, a factor previously demonstrated to be associated with

the progression and/or persistence of cervical neoplasia in HIV+ women over time (Pereira et al.,

2003), we also controlled for the impact of recent negative life event stress using an abbreviated

10-item version of the Life Experiences Survey (LES) (Sarason, Johnson, & Seigel, 1978)

described in detail elsewhere (Pereira et al., 2003). A significant relationship remained between

greater somatic depressive symptoms and greater odds of cervical neoplasia after controlling for

risk factors for neo lasia and life stress, OR = 2.19, 95% CI = 1.01 4.74, = 0.046 (not

shown).

Finally, to investigate whether an individual somatic depressive symptom was driving the

association between somatic depressive symptomatology and cervical neoplasia, correlational

analyses were conducted on each of the somatic BDI items and neoplasia. Results of these

analyses showed that only the BDI question regarding difficulty sleeping was significantly

correlated with cervical neoplasia (r = .313, p = .021). However, when the BDI question

regarding sleep was removed from the hierarchical logistic regression, the remaining somatic

depressive symptoms continued to be significantly associated with greater odds of presenting

with cervical neo lasia (OR = 2.27, = .049, 95% CI = 1.01-5.12 Thus, it a pears that the

constellation of somatic depressive symptoms and not necessarily difficulty sleeping is

associated with greater odds of presenting with cervical neoplasia.









Table 3-1 Comparison of continuous demographic and health variables in participants who provided full and partial data.


Potential control
variable
Age (years)
Yearly income ($)
Years of education
HIV viral load
(cells/mm3 [l0glo
transformed])
CD4+CD3+
(cells/mm3)


Respondents
mean (SD)
30.04 (8.45)
11,601 (8,089)
11.55 (1.23)


2.55 (1.93)

455.43 (285.47)


Non-respondents
mean (SD)
35.0 (7.55)
11,575 (9,877)
11.38 (2.47)


p-value
0.057
0.992
0.821


0.26


1.938
-0.010
-0.231


1.75 (2.18) -1.138


384.33 (318.05)


-.681


61 0.498


Table 3-2 Comparison of categorical demographic and health variables in participants who provided full and partial data.
Potential control
Variable r/ df p value
Race 4.298 7 0.745
Marital status 2.75 4 0.601
Presence of dysplasia 0.578 1 0.447
HIV clinical axis .535 2 0.765
HPV status 1.667 1 0.197









Table 3-3 Predicting presence of cervical neoplasia from depressive symptoms.

(Step number) Wald Odds p 95% confidence
predictor B statistic ratio Value interval
(1) Biological
variables Lower
HIV viral load
(cells/mm3 [l0glo
transformed]) .476 3.151 1.609 0.076 0.
High-risk HPV 1.634 3.007 5.126 .083.
CD4+CD3+
(cells/mm3) 0.000 0.057 1.000 0.812 0.
Smoking .001 2.103 1.001 0.147 1.
(2) Psychological variable
Full BDI score 0.175 2.977 1.191 .084 0.
N = 54. Significance of the model, X2 (5) = 16.724, p = .005. Nagelkerke R2 = .432


Upper


952 2.722
808 32.514

997 1.004
000 1.002

997 1.453










Table 3-4 Predicting presence of cervical neoplasia from cognitive/affective depressive symptoms.


(Step number) Wa
Predictor stat
(1) Biological
variables
HIV viral load
(cells/mm3 [l0glo
transformed]) 0.487
High-risk HPV 1.585
CD4+CD3+
(cells/mm3) 0.000
Smoking .001
(2) Psychological variable
Cognitive/affective
BDI score .169
N = 54. Significance of model, X2 (5)


lId
;istic


Odds
ratio


95% confidence
p value interval


Lower


Upper


3.462 1.627 0.063
3.036 4.88 0.081

0.040 1.000 0.841
2.486 0.1.001 .115


2.266 1.184 0.132
14.953, p =.011. Nagelkerke' s R2


0.974 2.716
.821 29.026

0.997 1.004
1.000 1.002


0.950 1.476


.396










Table 3-5 Predicting presence of cervical neoplasia from somatic depressive symptoms.


(Step number) W
Predictor sta
(1) Biological
variables
HIV viral load
(cells/mm3 [l0glo
transformed]) 0.472
High-risk HPV 1.307
CD4+CD3+
(cells/mm3) 0.001
Smoking .001
(2) Psychological variable
Somatic BDI score 0.791
N = 54. Significance of model, X2 (5)


ald
Itistic


Odds
ratio


95% confidence
p value interval


Lower


Upper


2.786
1.764

0.002
1.537

4.126
19.77 p


1.603 0.095
3.695 0.184

1.001 0.567
1.001 0.215

2.206 0.042
.001. Nagelkerke's R2 = .497


0.921 2.789
.537 25.423

0.998 1.005
1.000 1.002

1.028 4.733









CHAPTER 4
DISCUSSION

Previous research has shown that depression and depressive symptoms are associated

with negative health outcomes for individuals with HIV infection (Burack et al., 1993; Ickovics

et al., 2001; Mayne et al., 1996; Leserman et al., 1999; Leserman et al., 2002). However, very

little research has investigated the possible relationship between depressive symptoms and HIV-

specific pathophysiologic disease processes in women. This is a significant gap in the current

literature, because the relationship between depression and specific HIV disease outcomes may

help to explain the associations that have already been demonstrated between depression and

more global yet highly significant outcomes, such as HIV progression and mortality. By

identifying the specific disease processes that may underlie the previously demonstrated link

between depression and HIV progression and mortality, specific screening and interventions can

be tailored to provide the most effective and comprehensive treatments for HIV+ women.

The current study is the first, to our knowledge, to examine the relationship between

depressive symptoms and HPV-initiated cervical neoplasia, the pre-malignant stage of cervical

cancer. Cervical cancer is the most common AIDS defining malignancy in women with HIV

infection (Maiman et al., 1997). The progression of cervical neoplasia in HIV+ women has

significant clinical implications, as CINT II advances HIV+ women to symptomatic disease status

and CINT III advances HIV+ women to a clinical AIDS diagnosis. Fortunately, cervical neoplasia

is easily detectable via cervical cytology and histology, thus allowing for the initiation of

treatment prior to the development of invasive cervical cancer. In addition, cervical neoplasia is

initiated by HPV infection, a common, sexually-transmitted virus that is controlled by the

immune system and, by implication, potentially influenced by psychosocial factors that are

known to influence the immunosurveillance of latent viruses.









As expected, HR-HPV and cervical neoplasia were highly prevalent in our sample. HR-

HPV infection was detected in 78.2% of the study participants, and cervical neoplasia was

present in 81.8% of the participants. Participants in our sample included women who were

asymptomatic, as well as those with advanced HIV disease. Therefore, it is likely that these

results can be generalized to women at any stage of the HIV disease continuum.

Women in this study presented with wide variability in degree of depressive

symptomatology, ranging from endorsing no current depressive symptoms to endorsing

clinically-signifieant depressive symptomatology. It is possible that women with the most severe

depressive symptomatology were not adequately sampled, because they did not present for

routine obstetric and gynecologic care, refused research participation, or did not complete full

study procedures. However, in spite of the challenges of recruiting and retaining participants

with severe depressive symptomatology, 11% of our sample endorsed symptoms suggestive of

clinically significant depression.

Total depressive symptomatology was only marginally associated with cervical neoplasia

in this sample of HIV+ women with HPV infection and there was no relationship between the

cognitive/affective symptoms of depression and cervical neoplasia. Only greater levels of

somatic depressive symptoms were significantly associated with greater odds of cervical

neoplasia, specifically increasing the odds of cervical neoplasia by approximately two-fold. This

finding persisted after controlling for recent negative life event stress, a factor associated with

the progression and/or persistence of cervical neoplasia in our prior research.

This finding is consistent with research suggesting that African Americans, who comprised

the maj ority of our sample, may tend to manifest depression through primarily somatic

symptoms (Das et al., 2006). In addition, it is consistent with the wealth of research









demonstrating that women tend to present frequently with "atypical depression," which includes

somatic symptoms such as weight gain and problems with sleep (Bhatia & Bhatia, 1999). The

results of the current study also appear to be consistent with some published research on somatic

depression and HIV outcomes. Perkins et al. (1995) found that fatigue and insomnia were

associated with dysphoric mood and maj or depressive disorder in HIV+ individuals.

Furthermore, one large-scale, longitudinal study demonstrated that somatic depressive symptoms

were associated with progression to AIDS, progression to HIV-dementia, and shortened survival,

even after controlling for HIV medication use (Farinpour et al., 2003). Taken together, these

findings suggest that somatic depression may be a particularly important marker of depressive

disorders and a correlate of important disease outcomes in HIV.

Study Limitations

Caution must be used when interpreting our findings given our modest sample size,

undersampling of severely depressed women, and cross-sectional design, the latter of which

precludes the ability to establish whether somatic depression causes cervical neoplasia or vice-

versa. Of note, the BDI was administered to participants after they had been notified of their

Papanicolaou smear and cervical biopsy results. This was unavoidable given that (a) study

eligibility was based upon these results, and (b) colposcopic examinations were clinically

indicated, and thus it would have been unethical to withhold cytology/histology results from

participants for research purposes. Although this raises some concern that BDI results may be

confounded with CIN-related distress, it should be noted that only participants with no or grade I

(mild) cervical neoplasia were eligible for the study. In addition, approximately four to six

weeks typically elapsed between notification of cytology/histology results and administration of

the BDI, which assessed depressive symptomatology over the prior week only. Finally, an

examination of the BDI and PEAPS-Q scores demonstrated that there was no association










between distress related to the colposcopy and depressive symptoms (p > .05). In concert, these

factors may have restricted the degree of CIN-related distress that could be confounded with

depressive symptomatology. An additional limitation of this study is that several participants did

not have a cervical biopsy performed due the presence of clinical contraindications for biopsy. A

cervical biopsy is necessary to establish a diagnosis of cervical neoplasia, and it is possible that

cervical cytology may have underestimated the degree of cervical neoplasia present among these

parti cipants.

Future Directions

Future research should utilize prospective, longitudinal, and/or experimental designs to facilitate

the examination of possible causal mechanisms between depressive symptoms and cervical

neoplasia. For instance, somatic depression may increase odds of cervical neoplasia through

impaired immune functioning. Somatic depression may be associated with a shift in the

production of cytokines from a pattern that promotes cellular immunity (Thl cytokine

production: e.g., interferon-gamma, interleukin-2, tumor necrosis factor-alpha) to one that

promotes primarily humoral immunity (Th2 cytokines production: e.g., interleukin-4,

interleukin-10). This shift has been implicated in the progression of both HPV and HIV (Bais et

al., 2006; Kedzierska & Crowe,2001). Suppression of cellular immunity through a decreased

Thl cytokine response may allow for tumor growth and metastasis to occur (Rankin et al., 2003),

while enhancement of a Th2 cytokine response may promote the survival of cancer cells through

the prevention of programmed cell death ("apoptosis:") (Conticello et al., 2004).

Depression has also been strongly implicated in alterations (increases) in pro-

inflammatory cytokines, including IL-1P, IL-6, and IFN-yI, which are capable of inducing

sickness behaviors, including fatigue, lethargy, muscle and j oint pain, and anorexia (Dantzer,










2006), symptoms that overlap greatly with somatic depressive symptoms. In addition, recent

evidence has indicated that chronic inflammation, and thus an increase in the associated

cytokines, may be involved in carcinogenic processes (Antoni et al., 2006; Balkwill, Charles, &

Mantovani, 2005). Chronic inflammation has also been implicated specifically as a risk factor for

HPV persistence and progression to cervical cancer (Castle, 2004). Thus, bidirectional

relationships between somatic depression and cytokine production, on the one hand, and

cytokine production and cervical neoplasia on the other hand, may account for the present

findings. In the sample used for the current study, greater somatic depressive symptoms were

associated with lower CD4+CD3+ cell counts at study entry (r = -.286, p = .036).

Cognitive/affective depressive symptoms were not associated with CD4+CD3+ cell counts. In

addition, neither somatic nor cognitive/affective depressive symptoms were significantly

associated with HIV viral load, though there was a positive relationship between somatic

depressive symptoms and HIV viral load that approached significance (r = .243, p = .077).

While it is intriguing to consider that cytokine production may mediate the relationship

between somatic depressive symptoms and cervical neoplasia, it is equally possible that this

relationship may be accounted for by the effects of depression on health care behaviors, such as

Papanicolaou smear screening and medication adherence. Therefore, future research should be

guided by a comprehensive model that would allow the testing of (a) multiple mediators of the

relationship between somatic depression and cervical neoplasia, including both cytokine

production and health behaviors, and (b) bidirectional relationships among these variables.

In summary, the findings of the present study suggest that it may be important to assess the

presence and severity of depressive symptoms, most notably somatic depressive symptoms,

among HIV+ women attending gynecologic and obstetric clinics. Ultimately, the identification









and treatment of somatic depression among HIV+ HPV+ women may enhance health-related

quality of life in part via reduction in risk of cervical cancer.










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BIOGRAPHICAL SKETCH

Stacy Dodd graduated with honors from the University of Michigan in 2005, receiving a

Bachelor of Arts degree in Psychology. During her time at the University of Michigan, she

worked as a research assistant for the Families and Communities Together Coalition on a study

investigating the effects of a group intervention for women and children who had experienced

domestic violence. She also completed an undergraduate honors thesis on the worries of

childhood cancer patients and their mothers and the abilities of each to predict the worries of the

other.

Stacy began attending graduate school at the University of Florida in the department of

Clinical and Health Psychology in August 2005. She is focusing her research on psycho-

oncology, psychneuroimmunology, and women's health. She is currently pursuing her Ph.D. in

Clinical Psychology.