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Modern antiretroviral therapy (ART) has improved health and longevity for people living with HIV (PLWH). Despite substantial progress in medical management of HIV, PLWH experience elevated physical and psychosocial burdens. For example, more than 50% of PLWH experience pain (1), which continues to be a problematic and underaddressed symptom among PLWH (2) that detracts from their quality of life (3).
Bodily pain among PLWH can commonly include unique HIV-associated patterns, such as sensory neuropathy associated with HIV infection and early-generation ART, as well as patterns with less clear etiologies including musculoskeletal and multisite pain (4,5). Overall, PLWH report higher levels of pain than their HIV-negative peers (3,6). In a large cohort study, PLWH reported higher pain levels than those without HIV, and pain was associated with missed days of work and lower quality of life (3). PLWH who are older and those who have been receiving ART for longer periods of time seem to experience pain at higher rates than those who are younger or their similarly aged counterparts without HIV (4,6). This pattern may be due in part to greater accumulated physiological damage or exposure to earlier-generation ART medications that contribute to peripheral neuropathy. Pain is also associated with outcomes that signal vulnerability to poor health during the aging process, including greater healthcare utilization (4), higher likelihood of exhibiting prefrail or frail phenotypes (7), and lower self-rated physical function (8,9). Accordingly, studies of pain among older PLWH, typically defined as 50 years and older in the HIV literature, is especially needed.
In a recent publication that summarized input from a global task force, high-priority areas for advancing the science and clinical management of pain included understanding its etiology and exploring the influence of psychosocial factors on pain (10). The biopsychosocial model (11), which has been applied to pain in PLWH (12), is a well-established approach to guiding such work. This framework posits that biological, psychological, and social factors interact dynamically to impact the pain experience, which can in turn affect health outcomes and quality of life. As a result, investigating biobehavioral contributors to pain may inform avenues for improving quality of life for the growing number of older adults with HIV, who are at risk for poor pain-related health outcomes. Here, we focus on psychological symptoms and systemic inflammation as potential contributors, given that they are elevated among PLWH and consistently linked to pain in the broader literature.
PLWH often experience elevated rates of mental health symptoms, a pattern that likely has key consequences for bodily pain in older PLWH. Depression and pain frequently co-occur; higher rates of pain have been observed among individuals with depression (13,14). In a 4-year population-based study of older adults, those with more psychological symptoms (as measured by a composite of depressive and anxiety symptoms) were more likely to have worsening pain and other somatic symptoms than those fewer psychological symptoms; the effects of these symptoms were similar to or larger than the effects of obesity and smoking (15). Among PLWH on long-term opioid therapy, baseline depressive symptoms contributed to increases in pain interference (i.e., impact on functioning and normal activities) over the course of 1 year (16). The relationship between depressive symptoms and bodily pain is also bidirectional, such that experiencing pain is often a distressing experience that can worsen mental health over time (17,18).
Inflammation is another likely contributor to pain among PLWH (19). Even in the context of viral suppression, PLWH experience elevated levels of systemic inflammation compared with their counterparts without HIV (20). Multiple factors, including residual low-level viral replication, other coinfections (e.g., cytomegalovirus), and chronic immune activation, are posited to drive the persistent low-grade inflammation experienced by PLWH (21). Although the relationships between pain and inflammation are complex (spanning acute and chronic patterns, as well as peripheral and central mechanisms), studies suggest that systemic inflammation can promote pain along with other sickness behaviors (22), as well as alter pain perception and signaling pathways (23). For example, in experimental study designs, participants who received endotoxin to induce an inflammatory response had lower pain thresholds on several standardized pain tasks than those in a control condition (24,25); higher levels of cytokines interleukin 6 (IL-6) and interleukin 8 (IL-8) were related to higher pain ratings (25). In addition, systemic inflammation has been linked to various pain-related conditions (26–28) and depressive symptoms (29), suggesting that these factors are interconnected. However, the literature on links between systemic inflammation and pain in PLWH is relatively small. In initial studies among PLWH, pain was associated with higher levels of IL-6 and interleukin 1ß (30,31).
In summary, PLWH experience elevated levels of bodily pain that persists in the context of viral suppression with modern ART, which can negatively impact physical function. In addition, they experience higher levels of depressive symptoms and inflammation that may contribute to pain. Determining the extent to which depressive symptoms and inflammation are related to pain could inform novel approaches to assessment and intervention, especially for older adults who are most affected by pain yet are often underrepresented in HIV research. In the current study, we investigated links between biobehavioral factors and pain among older adults with HIV. We tested whether depressive symptoms and systemic inflammation were associated with bodily pain and investigated the relationship between pain and physical function, as indicated by subjective and objective measures. Based on a biopsychosocial conceptual model (12,19) and evidence suggesting that depressive symptoms and inflammation can contribute to pain (15,25), we then explored this potential pathway using cross-sectional data to test whether depressive symptoms and inflammation were associated with poorer physical function in part through worse pain.
METHODS ParticipantsParticipants were older adults with HIV who were recruited from the outpatient HIV clinics at Weill Cornell Medicine as part of the larger Research on Older Adults with HIV study (32). Data for this analysis are drawn from a substudy, which included a biomedical assessment; participants were invited to complete this portion of the study if they were 55 years or older, were English speaking, and had documented HIV infection. Exceptions were made to enroll two individuals who were 54 years of age and met the other inclusion criteria. Data were collected between June 2016 and March 2019. The analytic sample is composed of the 162 participants who had available data for the primary variables, pain and depressive symptoms; of these, inflammation data were available for 160 participants. Informed consent was obtained, and the study procedures were approved by the Weill Cornell Medicine Institutional Review Board.
Participants and ProceduresIn an initial study visit, participants completed a survey focusing on psychosocial factors as part of the Research on Older Adults with HIV study. They reported sociodemographic characteristics and depressive symptoms on the survey. Next, they attended a separate study visit to complete biomedical assessments, which were administered by trained research staff at the Weill Cornell Clinical and Translational Science Center. Participants were instructed to arrive fasting for 8 hours to the visit; blood samples were drawn and processed, and serum was stored at −80°C and then later assayed for inflammatory markers. At the visit, participants also completed objective measures of physical functioning (frailty, including grip strength, and gait speed) and answered self-report questions about past-month pain and physical functioning, as summarized below.
Measures Bodily PainParticipants reported bodily pain on the Medical Outcomes Study-HIV (MOS-HIV) survey (33). The bodily pain subscale is composed of two items; participants rated pain severity (“none” to “very severe”) and pain interference with normal activities (“not at all” to “extremely”) they experienced in the past month. To facilitate interpretation for this analysis, the bodily pain subscale was reverse-scored such that higher scores reflect worse pain.
Depressive SymptomsParticipants reported depressive symptoms on the 10-item Center for Epidemiological Studies Depression Scale (CESD-10) at the survey visit (34). They were asked to rate items such as “I was bothered by things that usually don’t bother me” and “I felt hopeful about the future (reverse-scored),” on a 0 to 3 scale. Continuous, total scores were calculated and used for analysis, with higher scores indicating greater depressive symptoms. Cronbach’s alpha was .83 in this sample.
Inflammation LevelsInflammation levels were measured using biomarker data for C-reactive protein (CRP) and proinflammatory cytokines IL-6, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ). The biomarker data were available as part of a larger study on psychosocial factors and inflammation, in which the cytokines were selected based on their expected relationships with depressive symptoms, loneliness, and stigma (29). Electrochemiluminescence-based assays were performed in the Weill Cornell Clinical and Translational Science Center Core Laboratory according to Meso Scale Discovery (Rockville, Maryland) kit instructions (K151STG and K15052G, respectively) using the MESO QuickPlex SQ120 Analyzer. Assays were run in duplicate with quality controls, with 10% repeated for confirmation. The intra-assay coefficients of variation for CRP, IL-6, TNF-α, and IFN-γ ranged from 2.4% to 6.4%, and the interassay coefficients of variation ranged from 5.0% to 10.2%. The detection limits of CRP, IL-6, TNF-α, and IFN-γ were 0.01 ng/ml, 0.10 pg/ml, 0.20 pg/ml, and 0.40 pg/mL, respectively. After examining inflammation data for outliers, winsorizing each biomarker variable to 3 standard deviations (SDs) from the mean (35,36), then log-transforming because of positive skew, a composite score for cytokine levels was computed as previously described (29). This strategy was used given moderate-to-strong correlations between IL-6, TNF-α, and IFN-γ cytokine levels (r = 0.25 to r = 0.52), and to facilitate interpretation and limit the number of statistical comparisons.
Physical Function Indicators Gait SpeedParticipants completed two 4-m walk trials at their usual speed (with assistive devices as needed), and gait speed was computed using the participant’s fastest trial time (37,38).
Grip StrengthGrip strength was measured using a dynamometer; participants completed three trials with their dominant hand, and the average of the trials was computed (39).
FrailtyFrailty was assessed according to the well-established Fried phenotype (40). Weak grip (assessed via dynamometer), slow walk (assessed via 4-m walk), unintentional weight loss (assessed via self-report), low physical activity (assessed via self-report), and exhaustion (assessed via self-report) components were assessed at the biomedical visit. Frailty criteria for each component were classified according to the cutoffs applied in a large cohort study of older adults with HIV (39). Participants who met the frailty criteria for 0 components were categorized as robust, those who met the criteria for 1 or 2 components were categorized as prefrail, and those who met the criteria for 3 or more components were categorized as frail. Participants with missing data on one or two components were considered evaluable (40) if their final frailty category would remain unchanged by the addition of the remaining scores.
Recent FallsTo assess history of recent falls, participants were asked “In the past six months, have you had a fall?” with response options of “yes” or “no.”
Self-Reported Physical FunctionParticipants completed the MOS-HIV survey, a well-validated quality-of-life instrument (33). Scores were computed for the Physical Function subscale according to the instrument manual. Participants were asked to rate how much their health limited them in a variety of daily activities (e.g., walking uphill or climbing a few flights of stairs), with response options “no, not limited at all,” “yes, limited a little” and “yes, limited a lot.” Higher subscale scores indicate better self-reported physical function, and Cronbach’s alpha was .86.
CovariatesBody mass index (BMI; in kilograms per meter squared) was calculated using height and weight measured at the biomedical visit. Smoking status was assessed via self-report on the psychosocial survey. Participants self-reported their gender identity on the survey; there was one transgender woman in the sample, and her data are included under female gender identity. To measure disease burden of HIV and comorbid conditions, scores on the validated Veterans Aging Cohort Study Index were calculated, a widely used measure of accumulated organ system injury among PLWH (41). Dichotomous variables indicating medication use were coded for selective serotonin reuptake inhibitor (SSRI) medications, analgesic opioid medications, and regular use of systemic anti-inflammatory medications (immunosuppressants, systemic glucocorticoids, antigout medications, and statins). These variables used medication lists that were reconciled by nurses at the biomedical study visit and were coded using the World Health Organization Anatomical Therapeutic Chemical classification system.
Statistical AnalysisAnalyses were conducted in SPSS, version 24.0 (IBM Corp., Armonk, New York). Pearson correlations were used to evaluate bivariate associations between depressive symptoms, inflammation, pain, and physical function measures. In follow-up adjusted analyses, depressive symptoms were tested as the key independent variable associated with pain levels while adjusting for age, sex, race, BMI, smoking, disease burden, SSRI use, opioid use, and years since HIV diagnosis. Covariates were selected based on their theoretical and established relationships with pain levels. Using the same covariates, relationships between pain and physical function indicators were examined in adjusted linear regression models for continuous outcomes (gait speed, grip strength, self-reported physical function) and adjusted logistic regression models for dichotomous outcomes (recent falls, prefrail or frail status). Similarly, adjusted linear regression models were used to test the relationship between pain and inflammation levels. We also conducted ancillary analyses adjusting for anti-inflammatory medication use and ancillary sensitivity analyses among those with CRP levels less than 10 mg/l (a common threshold for acute illness and analyses that focus on low-grade inflammation) (35,42,43), to determine whether the patterns were consistent in this subgroup. To determine whether the relationship between pain and the cytokine composite were driven by one or more of the individual cytokines, we conducted ancillary analyses to test the relationship between pain and individual cytokines in unadjusted and adjusted regression analyses.
Based on the observed relationships in the primary analyses and guided by the biopsychosocial model, exploratory analyses were conducted to examine pain as a mechanism linking depressive symptoms (or inflammation) and physical function. The PROCESS macro (version 3; model 4) was used to conduct mediation analyses (44), using mean-centered continuous variables and 10,000 bootstrap samples. Separate models included depressive symptoms (or inflammation levels) as the key predictor (x), bodily pain as the mediator (M), and continuous physical function measures individually as outcomes (y) in separate models, while adjusting for the same covariates as listed previously. Cases with missing data were excluded listwise for all models.
RESULTSOn average, participants were 61 years of age (SD = 5.66 years; range, 54–78 years) and had been diagnosed with HIV 23 years ago (SD = 5.69 years; range, 4–37 years). Other participant characteristics were: male (67%), Black (49%), and nonsmoking (84%). Most participants (85%) had undetectable virus levels (indicated by HIV-1 viral load <20 copies/ml).
On the MOS-HIV survey, 48% of participants rated their past-month bodily pain in the moderate to very severe range, 38% rated their pain as very mild or mild, and 14% reported having no pain in the past month. Pain interference with normal activities was rated as moderate or greater among 38% of participants. Fifty percent endorsed clinically significant levels of depressive symptoms, indicated by CES-D-10 scores of 10 or greater (34). Additional sample characteristics are summarized in Table 1.
TABLE 1 - Demographic and Key Variables for Participants in Sample (n = 162) Characteristic Mean (SD), Mdn (IQR), or n (%) Age, y 61.01 (5.66) Gender Female 53 (33%) Male 109 (67%) Race Black 80 (49%) White 51 (32%) Asian or Pacific Islander 3 (2%) Biracial or multiracial 25 (15%) Ethnicity Hispanic/Latino 42 (26%) Non-Hispanic/Latino 100 (62%) Education level ≤12 y 48 (30%) >12 y 111 (68%) Viral load <20 copies/mL 137 (85%) 20–50 copies/mL 9 (5%) ≥50 copies/mL 16 (10%) Time since HIV diagnosis, y 23.36 (5.69) Disease burden (VACS Index score) 33.15 (18.21) BMI, kg/m2 28.35 (7.07) Current smoking (yes) 26 (16%) SSRI medication use (yes) 18 (11%) Opioid medication use (yes) 31 (19%) Anti-inflammatory medication use (yes) a 85 (53%) Pain (MOS-HIV subscale, reverse-coded) 35.66 (24.76) Depressive symptoms (CESD-10 scores) 10.00 (6.37) Inflammation biomarkers, Mdn (IQR) CRP (raw values), mg/l 2.47 (1.19 to 5.53) IL-6 (raw values), pg/ml 0.92 (0.61 to 1.42) TNF-α (raw values), pg/ml 3.01 (2.38 to 3.94) IFN-γ (raw values), pg/ml 3.39 (1.99 to 6.18) Composite cytokine levels b −0.01 (−0.54 to 0.52) Gait speed (best trial), m/s 0.90 (0.23) Grip strength (average of 3 trials), kg 31.68 (8.72) Self-reported physical function (MOS-HIV subscale) 65.81 (26.74) Fall in past 6 mo (yes) 36 (22%) Prefrail or frail status 109 (67%)SD = standard deviation; Mdn = median; IQR = interquartile range; VACS = Veterans Aging Cohort Study Index; BMI = body mass index; SSRI = selective serotonin reuptake inhibitor; MOS-HIV = Medical Outcomes Study-HIV survey; CESD-10 = 10-item Center for Epidemiological Studies Depression Scale; CRP = C-reactive protein; IL = interleukin; TNF-α = tumor necrosis factor α; IFN-γ = interferon-γ.
% indicates percentage of those with available data for each variable. Data were missing for some participants for race (n = 3), ethnicity (n = 20), education (n = 3), gait speed (n = 1), falls (n = 2), grip strength (n = 5), and frailty status (n = 2).
a Indicates regular use of systemic anti-inflammatory medications (immunosuppressants, systemic glucocorticoids, antigout medications, and statins).
b Composite cytokine levels were computed by standardizing the log-transformed, winsorized inflammation variables to index z scores for each cytokine (IL-6, TNF-α, and IFN-γ), then averaging these three standardized variables.
Bivariate analyses are summarized in Table 2. Those with more depressive symptoms had worse pain than those with fewer depressive symptoms (r = 0.33, p < .001). The association between depressive symptoms and pain remained statistically significant in the adjusted regression model, as detailed in Table 3 (B = 1.31, SE = 0.28, p < .001). The set of independent variables in the adjusted model (age, sex, race, BMI, disease burden, current smoking, opioid medication, SSRI medication, time since HIV diagnosis, and depressive symptoms) explained 30.5% of the variance in pain levels (F(10,148) = 6.48, p < .001). The pattern of results did not change when anti-inflammatory medication use was added to the model. Bivariate correlations were also consistently observed between depressive symptoms and physical function indicators (Table 2).
TABLE 2 - Bivariate Pearson Correlations Between Pain, Depressive Symptoms, Inflammation, and Physical Function Indicators [1] [2] [3] [4] [5] [6] [7] [8] [9] [1] Bodily pain subscale — [2] Depressive symptoms 0.33** — [3] Composite cytokine levels 0.25* 0.24* — [4] CRP (log-transformed) 0.03 −0.05 0.40** — [5] Gait speed −0.32** −0.23* −0.17* −0.13 — [6] Grip strength −0.25* −0.20* −0.10 −0.11 0.26* — [7] Fall in past 6 mo 0.39** 0.31** 0.06 −0.02 −0.21* 0.02 — [8] Self-rated physical function −0.60** −0.35** −0.31** −0.19* 0.42** 0.29* −0.34** — [9] Prefrail/frail status 0.44** 0.43** 0.18* 0.02 −0.40** −0.30** 0.21* −0.50** —CRP = C-reactive protein.
* p < .050.
** p < .001.
MOS-HIV = Medical Outcomes Study-HIV survey; BMI = body mass index; VACS = Veterans Aging Cohort Study Index; SSRI = selective serotonin reuptake inhibitor.
Higher composite cytokine levels were associated with worse pain (r = 0.25, p = .002). There were not statistically significant associations between CRP levels and pain levels. The association between composite cytokine levels and pain remained statistically significant in the adjusted regression models, as detailed in Table 4 (B = 5.70, SE = 2.54, p = .027). The set of independent variables in the adjusted model (age, sex, race, BMI, disease burden, current smoking, opioid medication, SSRI medication, time since HIV diagnosis, and composite cytokine levels) explained 21.6% of the variance in pain levels (F(10,146) = 4.03, p < .001). We also conducted ancillary sensitivity analyses in the subset of participants with CRP values less than 10 mg/l (n = 143). Using this common approach for focusing on chronic low-grade inflammation, the pattern of results was the same as discussed previously. Similarly, the pattern of results did not change when anti-inflammatory medication use was added to the model.
TABLE 4 - Unadjusted and Adjusted Linear Regression Models Testing the Relationship Between Composite Cytokine Levels and Pain Dependent Variable: MOS-HIV Pain Subscale Independent Variable B SE t p R 2 Unadjusted model Composite cytokine levels 7.69 2.41 3.19 .002 0.06 Adjusted model Step 1 0.19 Age (years) −0.59 0.38 −1.58 .12 Gender (male) −5.96 4.36 −1.37 .17 Race (White) 5.60 4.40 1.27 .21 BMI (kg/m2) 0.44 0.27 1.66 .10 Disease burden (VACS) 0.19 0.13 1.48 .14 Current smoking (yes) 8.61 5.09 1.69 .093 Opioid medication (yes) 19.45 4.87 3.99 <.001 SSRI medication (yes) −4.57 6.11 −0.75 .46 Time since HIV diagnosis (years) 0.28 0.34 0.81 .42 Step 2
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