JAIDS Journal of Acquired Immune Deficiency Syndromes:
The Influence of Psychosocial Characteristics and Race/Ethnicity on the Use, Duration, and Success of Antiretroviral Therapy
Pence, Brian Wells PhD, MPH*†; Ostermann, Jan PhD*†‡; Kumar, Virender PhD§; Whetten, Kathryn PhD, MPH*†‡; Thielman, Nathan MD, MPH*∥; Mugavero, Michael J MD, MHSc¶
From the *Health Inequalities Program, Center for Health Policy, Duke University, Durham, NC; †Terry Sanford Institute of Public Policy, Duke University, Durham, NC; ‡Department of Community and Family Medicine, Duke University, Durham, NC; §Westat, Rockville, MD; ∥Division of Infectious Diseases and International Health, Department of Medicine, Duke University, Durham, NC; and the ¶Division of Infectious Diseases, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
Received for publication March 28, 2007; accepted September 10, 2007.
Supported in part by the National Institute of Mental Health (NIMH), the National Institute of Drug Abuse (NIDA), and the National Institute of Nursing Research (NINR); grant 5R01MH061687-05 of the National Institutes of Health, and grant 1R21 AA015052-01 A1 from the National Institute of Alcoholism and Alcohol Abuse. N. Thielman receives support from the AIDS Clinical Trial Group (V01-39156).
Correspondence to: Brian Wells Pence, PhD, Center for Health Policy, Box 90253, Duke University, Durham NC 27708 (e-mail: firstname.lastname@example.org).
Background: Expanded access to antiretroviral therapy (ART) has produced dramatic reductions in HIV-associated morbidity and mortality. Disparities in access to and benefit from ART have been observed by race, gender, and mental health status, however.
Methods: From 2001 to 2002, 611 HIV-positive patients were consecutively recruited from 5 southeastern US states and followed for 3 years. We evaluated demographic and psychosocial predictors of probability of receiving ART among all those eligible for ART (on ART, CD4 <350 cells/mm3 or viral load [VL] >55,000 copies/mL in the year preceding enrollment), time to first ART discontinuation among those on ART, and time to VL >400 copies/mL among those on ART with VL <400 copies/mL at enrollment.
Results: Of 611 participants, 474 consented to medical record abstraction and had known ART status at enrollment; 81% (385 of 474) of all participants and 89% (385 of 435) of ART-eligible participants were receiving ART at enrollment. In multivariable analyses, ART receipt was associated with greater age (adjusted odds ratio = 1.92 per 10 years, 95% confidence interval: 1.23 to 3.01), fewer recent stressful life events (odds ratio = 0.68, 95% confidence interval: 0.51 to 0.92), less alcohol use (odds ratio = 0.64, 95% confidence interval: 0.46 to 0.90), and greater perceived self-efficacy (OR = 2.82, 95% confidence interval: 1.41 to 5.62). No psychosocial characteristics were associated with ART discontinuation or virologic failure. No racial/ethnic or gender disparities were observed in ART receipt; however, minority racial/ethnic groups were faster to discontinue ART (adjusted hazard ratio = 2.44, 95% confidence interval: 1.33 to 4.49) and experience virologic failure (adjusted hazard ratio = 2.01, 95% confidence interval: 1.09 to 3.71).
Conclusions: Patients with unfavorable psychosocial profiles were less likely to be on ART, perhaps attributable to providers' or patients' expectations of readiness. Psychosocial characteristics were not associated with ART discontinuation or virologic failure, however, possibly reflecting the selection process involved in who initiates ART. Racial disparities in ART discontinuation and virologic failure merit further attention.
Advances in HIV care and the widespread availability of antiretroviral medications have resulted in dramatic reductions in HIV-associated morbidity and mortality. Not all groups have benefited equally from these advances, however. Multiple studies have identified lower likelihood of receipt of antiretroviral therapy (ART) among women and members of racial/ethnic minority groups in the United States.1-3 Independent of race and gender disparities, comorbid mental health and substance use disorders also seem to reduce the likelihood of a patient receiving ART,3-6 perhaps because of providers' or patients' decisions to defer ART until perceived barriers to medication adherence have been addressed.7,8
Disparities have also been identified in HIV-related clinical outcomes, particularly related to psychosocial factors. Mental illness and substance (including alcohol) use disorders affect most HIV-positive patients9 and predict more rapid discontinuation of ART,10 delayed virologic response and more rapid virologic failure in those initiating ART,11-13 and increased disease progression and mortality.14,15 An emerging body of literature also documents the high prevalence of psychosocial trauma, such as childhood sexual or physical abuse in HIV-positive patients,16,17 and associations of trauma history with reduced ART adherence and worse clinical outcomes.18,19 Meanwhile, greater psychologic resources, such as positive affect and expectancy about health outcomes, may protect against disease progression and mortality.20
In addition to the growing attention to psychosocial mediators of HIV outcomes, considerable interest has emerged in better understanding the HIV epidemic in the southeastern US.21,22 For some years, the Southeast has been the US region with the fastest-growing HIV epidemic: in 6 contiguous southeastern states whose epidemics share similar demographics and transmission characteristics (North Carolina, South Carolina, Georgia, Alabama, Mississippi, and Louisiana), 23 reported new cases of AIDS increased 36% from 2000 to 2005 compared with a 2% increase in the rest of the South and a 6% decrease in other regions of the United States.24,25 The HIV epidemic in the Southeast is characterized by relatively high incidence in persons exposed by means of heterosexual sexual intercourse and in women, minorities, the poor, and those living in rural areas. Relatively little research on patterns of ART use and effectiveness has been conducted in the US Southeast. Of 26 studies of ART utilization recently reviewed by Palacio and colleagues,1 no studies were located exclusively in this region and only 1 multisite study, dating from 1991, included multiple recruitment sites in the Southeast.
In this article, we present results from the Coping with HIV/AIDS in the Southeast (CHASE) study, a longitudinal study following 611 HIV-positive individuals engaged in clinical care from 5 southeastern states for over 3 years. The CHASE study primarily sought to examine the influence of sociodemographic and psychosocial characteristics on processes of care and clinical outcomes. Our goal with this analysis was to examine sociodemographic and psychosocial predictors of ART utilization, discontinuation of ART, and virologic failure.
Sample and Procedures
The CHASE study recruited HIV-infected patients who received care at 1 of 8 infectious disease clinics in 5 southern states (Alabama, Georgia, Louisiana, North Carolina, and South Carolina) and has been described in detail previously.18 Briefly, the study's primary goal was to examine the sociodemographic characteristics, coping strategies, life histories, and care utilization patterns of persons receiving HIV-related care outside the 3 major cities (Atlanta, Charlotte, and New Orleans) in the Southeast. Consecutive sampling of patients was used to minimize recruitment/volunteer bias and to yield a study cohort reflective of patients engaged in clinical care in this region. From December 2001 through April 2002, 611 patients enrolled in the CHASE study, representing 79% of patients approached. Sociodemographic and psychosocial information was obtained through structured interviews by trained and field-certified interviewers using validated instruments at enrollment and after 9, 18, and 27 months. Interviews lasted approximately 2 hours and were conducted in a private location of the participant's choosing, given the sensitive nature of the material. Trained health care providers recorded clinical information from patients' medical records on standardized abstraction forms for the 527 CHASE participants (82%) who provided consent for chart abstraction. Medical record data covered the entire follow-up period. This study was approved by Institutional Review Boards at Duke University and all recruitment sites.
We considered 3 outcome measures: (1) of those eligible for ART at enrollment, the probability of being on ART; (2) of those on ART at enrollment, the time from enrollment to the first interruption of ART; and (3) of those on ART and with an HIV RNA plasma viral load (VL) <400 copies/mL at enrollment, the time from enrollment to virologic failure (first VL ≥400 copies/mL). For comparability with prior studies3,26 and in accordance with clinical recommendations in effect at the time of recruitment,27 we defined as ART eligible all patients who (1) were on ART at enrollment or (2) had a CD4 count <350 cells/mm3 or VL >55,000 copies/mL within the 12 months before enrollment. Complete ART histories and laboratory values were collected by means of medical record abstraction. ART histories were reviewed for consistency by a board-certified infectious diseases physician, and queries were resolved through consultation with the original chart.
Sociodemographic variables obtained from the baseline interview included self-reported age, gender, race/ethnicity, and health insurance status.
Clinical characteristics, including CD4 cell count and VL at enrollment, whether the current ART regimen was the participant's first, and length of time on the current regimen, were determined from the medical record. Antiretroviral medication adherence was measured by patient self-report using a modified version of the Adult AIDS Clinical Trials Group Adherence Instrument.28 For the purposes of this analysis, patients were considered nonadherent if they reported missing any doses of their HIV medications during the previous 7 days.28 This definition has been previously demonstrated to correlate with virologic response in this sample.18
Psychosocial measures have been described in detail previously.18,29 In brief, the psychosocial trauma measure, adapted from prior research,30,31 assigns 1 point for each of 15 types of possible lifetime traumatic experiences (eg, sexual abuse, physical trauma, childhood physical and emotional neglect, non-HIV-related life-threatening illnesses or injuries, murder of a close family member, death of a child, and death of a spouse/partner). The measure could range from 0 to 15. This specification of the number of types of traumatic events experienced has been used widely and predicts multiple negative health outcomes.18,29,32 Depressive symptoms were measured with the depression subscale of the Brief Symptoms Inventory (BSI); this subscale has adequate internal consistency (Cronbach α = 0.85) and test-retest reliability (Cronbach α = 0.84).33 Subscale scores were converted to gender-specific T scores ranging from 0 to 100, with a change of 10 units corresponding to a shift of 1 standard deviation in the normative population.33 Recent severe stressful life events during the 9 months preceding the interview were measured using a modified version of the Life Events Survey (LES),34 modified to include only those events that were considered moderately to severely stressful based on our previous studies with interviewer-based objectively rated stresses.35 For the current analysis, we focused only on severe stresses in the past 9 months, including divorce or separation from spouse/partner, death or serious illness of immediate family member, major financial problems (eg, foreclosure, not enough money for basic necessities), physical or sexual assault, or more than a week in prison. The number of recent severe stressful events could range from 0 to 8. Recent alcohol and drug use was measured with the Addiction Severity Index (ASI); standard scoring procedures were followed to generate alcohol and drug composite scores ranging from 0 to 100.36 The reliability and validity of the ASI are well established.36,37 Social support was assessed with the Medical Outcomes Study Social Support Survey,38 and the Pearlin Self-Efficacy Scale was used to measure self-efficacy.39 Both measures have been shown to have high internal and construct validity.
We modeled the probability of being on ART among ART-eligible participants using bivariable contingency tables and multiple logistic regression. We modeled the time from baseline to (1) first ART discontinuation and (2) virologic failure using survival analysis techniques, including Kaplan-Meier functions, log-rank tests, and Cox proportional hazard models. In modeling time to ART discontinuation, participants who did not discontinue were censored at the end of follow-up. In modeling time to virologic failure, participants who maintained virologic suppression were censored at the end of follow-up, ART discontinuation, or at the last VL measure before a gap of 12 months or more in VL measures. For each multivariable model, we included sociodemographic (age, gender, race, and health insurance status), clinical (time on current regimen and whether the current regimen was the participant's first), and psychosocial (depression, alcohol and drug use, lifetime trauma, recent stress, social support, and self efficacy) covariates deemed of a priori interest. We observed moderate correlation between some pairs of psychosocial variables (ρ ranged in absolute value from 0.01 to 0.35; the most highly correlated pairs were social support and depressive symptoms [ρ = −0.35], alcohol and drug scores [ρ = 0.31], and trauma and stress [ρ = 0.260]; all other ρ correlations were <0.25). We therefore compared the full model with a set of separate models, each containing 1 psychosocial variable and all sociodemographic and clinical covariates. Finally, in considering ART discontinuation and virologic failure, we compared models with and without controlling for adherence to assess its role in mediating observed relations.
We included site fixed effects in all models to account for variation in prescribing patterns and covariates across sites. For all models, we confirmed that key distributional assumptions were met. In particular, for the proportional hazard models, we verified the assumption of proportionality in the log hazard by examining plots of Schoenfeld residuals for each covariate in the final model and evaluated interaction terms with the natural logarithm of analysis time for covariates that seemd to violate the proportional hazard assumption.40
In sensitivity analyses, we assessed whether results changed substantively when modeling probability of being on HAART (instead of being on ART) and time to HAART discontinuation (instead of ART discontinuation). Here, HAART was defined as a combination of at least 2 nucleoside reverse transcriptase inhibitors in addition to at least 1 of the following: protease inhibitor, nonnucleoside reverse transcriptase inhibitor, or abacavir, consistent with clinical recommendations effective at the time.27 We also considered an alternate definition of virologic failure that excluded “blips”: a single VL measure ≥400 copies/mL but <1000 copies/mL immediately followed by a VL <400 copies/mL.
Of 611 CHASE participants, 84 did not provide consent for medical record abstraction, 46 were of uncertain ART status at study enrollment, and 7 had no CD4 cell count or VL data available for the 12 months before enrollment (Fig. 1). Additionally, 39 individuals were not on ART and were not medically eligible for ART at enrollment. Analysis 1 thus includes 435 individuals on ART or considered ART eligible at enrollment, including 385 participants on ART and 50 participants not on ART but ART eligible. Most participants on ART were on HAART (n = 338 [88%]). Analysis 2 models time from enrollment to ART discontinuation among the 385 participants on ART at enrollment. Analysis 3 models time from enrollment to virologic failure among the 194 participants on ART and with a VL <400 copies/mL at enrollment.
Participants were primarily 30 to 50 years old (mean ± standard deviation: 40.4 ± 8.6) (Table 1). Thirty percent of the participants were female. Sixty-one percent were African American, with the remainder primarily white. Fifty-four percent were on public health insurance, and 21% were uninsured. The sample was fairly treatment experienced: of those on ART at enrollment, only 39% were on their first ART regimen and 47% had been on their current regimen for a year or more. Lifetime traumatic experiences (mean ± standard deviation: 3.1 ± 2.4) and recent severe stressful events (mean ± standard deviation: 1.4 ± 1.2) were common; although comparable statistics for the general population are not available, we note that the prevalence of childhood sexual abuse in this sample (35% of women and 29% of men) was high relative to general population estimates (20% of women and 5% of men).41 Those included in the analysis were comparable to those not included on all measured demographic and psychosocial characteristics (P > 0.05 for all comparisons; data not shown).
Eighty-one percent of all participants (385 of 474) and 89% of medically eligible participants (385 of 435) were receiving ART at enrollment. Compared with all those eligible for but not receiving ART, those receiving ART at enrollment were on average older and were more likely to have private health insurance, and they had higher CD4 cell counts, less stress, less alcohol use, and greater perceived self-efficacy (Table 2). Of all those on ART at enrollment, those with suppressed VL were more likely to be male and white and to have private health insurance, and they had higher CD4 counts, fewer depressive symptoms, and less stress on average than those with unsuppressed VL.
Probability of Being on ART
Of the 435 participants on or eligible for ART, probability of being on ART was associated in multivariable analyses with greater age (adjusted odds ratio [aOR] = 1.92 per 10 years, 95% confidence interval [CI]: 1.23 to 3.1), fewer recent stressful life events (aOR = 0.68 per event, 95% CI: 0.51 to 0.92), less alcohol use (aOR = 0.64 per 10 points on 100-point scale, 95% CI: 0.46 to 0.90), and greater perceived self-efficacy (aOR = 2.82, 95% CI: 1.41 to 5.62) (Table 3).
Of all participants on ART at baseline, those of minority race/ethnicity discontinued ART more rapidly than white non-Hispanics (adjusted hazard ratio [aHR] = 2.44, 95% CI: 1.33 to 4.49; Fig. 2A). Trends were observed for faster ART discontinuation in women compared with men (aHR = 1.49, 95% CI: 0.91 to 2.45; P = 0.11) and for slower ART discontinuation in those with private health insurance compared with those with public or no insurance (aHR = 0.58, 95% CI: 0.31 to 1.09; P = 0.09). No clinical or psychosocial characteristics were associated with ART discontinuation. In a separate model additionally controlling for adherence, no point estimate changed appreciably but better adherence was associated with a slower rate of ART discontinuation (aHR = 0.58, 95% CI: 0.34 to 0.99).
Of all participants on ART and with suppressed VL at baseline, those of minority race/ethnicity demonstrated virologic failure more rapidly than white non-Hispanics (aHR = 2.01, 95% CI: 1.09 to 3.71; see Fig. 2B). No clinical or psychosocial characteristics were associated with time to virologic failure. In a separate model additionally controlling for adherence, no point estimate changed appreciably and adherence was not associated with virologic failure.
When estimating a set of separate models each containing 1 psychosocial variable in addition to all sociodemographic and clinical variables to address potential collinearity, no estimate changed appreciably. Consistent with the primary analysis, lifetime trauma, depression, drug use, and social support did not predict any outcome whereas recent stress, alcohol use, and self-efficacy predicted only the probability of being on ART. When attention was restricted to participants receiving or eligible for HAART rather than ART, the observed associations with stressful life and events, alcohol consumption were no longer statistically significant (P = 0.10 and P = 0.12, respectively) whereas self-efficacy remained positively associated with HAART receipt; those with private insurance were more likely to be on HAART than those without (aOR = 2.54, 95% CI: 1.10 to 5.87; data not shown). When considering time to discontinuation of HAART rather than ART, the trend toward a disadvantage of women relative to men became statistically significant (aHR 1.83, 1.14 to 2.95, P = 0.01) while the differences by race became a trend (aHR = 0.61, 95% CI: 0.36 to 1.09; P = 0.07). When modeling virologic failure but permitting “blips,” the advantage of whites relative to nonwhites became a trend (aHR = 0.54, 95% CI: 0.27 to 1.09; P = 0.09).
The present study contributes to the existing literature on ART utilization and effectiveness in several ways. First, we examined 3 important treatment-related outcomes in a single cohort (ART use, ART duration, and virologic failure). Further, we evaluated a range of key sociodemographic and psychosocial predictors of these treatment outcomes. In addition, we report data from a cohort representing an understudied and epidemiologically important US population, those living with HIV in the rural and semiurban Southeast.
Overall, a high proportion (89%) of patients medically eligible for ART were receiving ART. We identified important psychosocial predictors of receiving ART among those who were eligible. Those with less alcohol use, greater perceived self-efficacy, and lives marked by fewer severe stresses were more likely to be on ART if eligible. Interestingly, we did not observe statistically significant differences in ART receipt according to current depressive symptoms, current drug use, lifetime trauma exposure, or strength of social support. We do note that all point estimates for these variables were in the expected direction, although the modest sample size resulted in relatively wide confidence intervals. Previous research has generally identified a disadvantage in receipt of ART for individuals with concurrent mental health and substance use disorders,3-6 although comparison with other studies is difficult because of differing time frames, source populations, and measures.
Contrary to expectations, no psychosocial factors were associated with discontinuing ART among those on ART or with virologic failure among those on ART with suppressed VL. This finding may indicate that patients and providers are making effective decisions about who initiates ART. Additionally, those on ART are likely to be more heavily engaged in clinical care than those not on ART; therefore, patients with depression or substance abuse may be more likely to be receiving appropriate treatment (although this hypothesis could not be tested in the current study). We note that psychosocial characteristics were measured not at the time of regimen initiation but at the time of CHASE study enrollment, and the cohort may therefore reflect a “survivor's bias” (those remaining on ART at the time of enrollment are not representative of all those who started ART at comparable times).
Several prior studies have reported increased discontinuation and virologic failure among participants with concurrent psychiatric comorbidity including alcohol use, although conflicting reports exist.10-13 Of particular note, a report from a large HIV clinic offering on-site psychiatric services found that patients with a documented and treated psychiatric disorder were more likely to receive ART and to continue it for at least 6 months.42 This finding may reflect the fact that the “treated psychiatric disorder” group was likely more heavily engaged in clinical care, and thus predisposed to succeed on ART.
We considered multiple psychosocial measures in this analysis, some of which were moderately correlated. Results were consistent whether psychosocial dimensions were considered jointly or separately, suggesting that the inclusion of multiple measures did not lead to unstable results as a result of collinearity or to distal effects being masked by the inclusion of more proximal mediators.
A lower proportion of women and racial/ethnic minorities were on ART relative to men and white non-Hispanics in this sample, although the differences were small and not statistically significant (86% of women vs. 90% of men; 87% of minorities vs. 91% of whites). Most published studies have reported racial and gender disparities in ART receipt, although the magnitude of disparities in recent studies has not been large.1 Gender and racial disparities in ART receipt were reported from a multisite cohort recruited in 2001 (comparable in time to the CHASE study enrollment period); the modest absolute differences in utilization (80.9% of women vs. 84.9% of men; 82.2% of African Americans vs. 83.7% of whites) were statistically significant in this large sample (n > 10,000).3 Two of the 10 sites in this study were large metropolitan areas in the South.
In the present study, racial and ethnic minorities did demonstrate faster rates of ART discontinuation if on ART at enrollment and faster rates of virologic failure if virologically suppressed at enrollment. Some but not all previous studies have identified disadvantages of minority populations in maintenance of HAART and virologic suppression.42,43 A report from AIDS Clinical Trials Group (ACTG) 5095, a randomized clinical trial, indicated that African-American non-Hispanics initiating efavirenz-based regimens were significantly more likely to experience virologic failure and had faster rates of discontinuation of their initial regimen than white non-Hispanics, differences that did not seem to be attributable to differential toxicity or viral mutations.43
Taken together, the findings reported here of small differences by race in ART utilization but important disadvantages for minorities in ART maintenance and virologic failure may reflect barriers to accessing a continuous supply of antiretrovirals in the South. The challenge of sustaining effective HIV treatment for this population is suggested by the fact that only 50% (194 of 385) of those patients on ART had a VL <400 copies/mL at enrollment. The high proportion of participants on the expensive antiretrovirals is perhaps surprising, given that only one quarter of participants had private health insurance and one quarter had no insurance coverage at all at the time of enrollment, and likely reflects the effective safety net role played by payers such as Medicaid, state-run AIDS drug assistance programs (ADAPs), clinical trials, and charity care programs run by pharmaceutic companies and hospitals. Patients who rely on such sources for their medication may be more likely to face gaps in coverage, however, with resulting inability to obtain antiretrovirals. For example, many patients on Medicaid periodically lose coverage (as frequently as every 6 months) and enter what is known as the “spend-down” period, during which they must incur a certain amount of out-of-pocket medical expenses before becoming eligible for Medicaid again. These spend-down policies lead to a predictable pattern of high medical expenses in the first and last months of Medicaid coverage and low expenses (ie, gaps in care) during spend-down months.44 Thirty-one states have Medicaid spend-down provisions, including 4 of 5 CHASE study states. Lack of private health insurance disproportionately affected racial/ethnic minorities in this sample: 83% of minorities lacked private health insurance at enrollment compared with 60% of whites. Although we controlled for insurance type in this analysis, we only had a measure of insurance status at the time of enrollment, which may not have adequately captured the longitudinal dynamics of insurance coverage over the follow-up period.
Some caution should be used in interpreting the results of this study. First, the analysis of probability of being on ART is cross-sectional and should not be interpreted etiologically. Second, the statistical significance of results showed some sensitivity to certain analytic choices, for example, when modeling HAART receipt rather than ART receipt, although point estimates generally remained consistent in direction. We decided it was appropriate to model ART receipt, given most patients receiving ART were receiving HAART and the remainder may have been receiving optimized therapy, given their particular clinical scenario, because a substantial fraction of CHASE study participants were heavily ART experienced at enrollment.
It should also be noted that the analyses of time to treatment discontinuation and virologic failure used as their starting point the date of CHASE study enrollment, which occurred at varying points in patients' HIV treatment history. Because the CHASE sampling frame was defined at a given point in calendar time rather than at ART initiation for each patient, time-to-event analyses that used the (historical) date of ART initiation as their starting point would face a left-censoring challenge. To address the use of date of enrollment as our starting point, we considered measures of prior treatment experience and treatment duration at enrollment; these variables did not predict outcomes and did not affect coefficients of other variables in the models.
Although the availability and use of antiretroviral medications have expanded greatly in the past decade, important groups of patients continue to face disadvantages in their use. HIV clinical care systems should continue to strive to address the psychosocial needs of their patients to ensure their ability to remain engaged in clinical care and fully benefit from ART. Continued attention should focus on the dynamics determining differential use and effectiveness of ART in minority populations, particularly sustaining continuous access to expensive medications for those with unstable insurance coverage.
The authors thank the CHASE study patients for their participation. The authors have no relevant conflicts of interest to report.
All authors had full access to all study data. B. W. Pence takes full responsibility for the integrity of the data and the accuracy of all data analyses. B. W. Pence, J. Ostermann, V. Kumar, K. Whetten, N. Thielman, and M. J. Mugavero were responsible for study concept and design. K. Whetten and N. Thielman were responsible for acquisition of data. B. W. Pence, J. Ostermann, V. Kumar, K. Whetten, N. Thielman, and M. J. Mugavero were responsible for analysis and interpretation of data. B. W. Pence was responsible for drafting of the manuscript. J. Ostermann, V. Kumar, K. Whetten, N. Thielman, and M. J. Mugavero were responsible for critical revision of the manuscript for important intellectual content. B. W. Pence was responsible for statistical analysis. K. Whetten obtained funding.
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