Diabetes Changes Symptoms Cluster Patterns in Persons Living With HIV

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Diabetes Changes Symptoms Cluster Patterns in Persons Living With HIV Julie Ann Zuniga, PhD, RN* Eliezer Bose, PhD, AGACNP-BC Jungmin Park, PhD, RN M. Danet Lapiz-Bluhm, PhD, RN Alexandra A. Garcıa, PhD, RN, FAAN Approximately 10-15% of persons living with HIV (PLWH) have a comorbid diagnosis of diabetes mellitus (DM). Both of these long-term chronic conditions are associated with high rates of symptom burden. The purpose of our study was to describe symptom patterns for PLWH with DM (PLWH1DM) using a large secondary dataset. The prevalence, burden, and bothersomeness of symptoms reported by patients in routine clinic visits during 2015 were assessed using the 20-item HIV Symptom Index. Principal component analysis was used to identify symptom clusters. Three main clusters were identified: (a) neurological/psychological, (b) gastrointestinal/ flu-like, and (c) physical changes. The most prevalent symptoms were fatigue, poor sleep, aches, neuropathy, and sadness. When compared to a previous symptom study with PLWH, symptoms clustered differently in our sample of patients with dual diagnoses of HIV and diabetes. Clinicians should appropriately assess symptoms for their patients’ comorbid conditions. (Journal of the Association of Nurses in AIDS Care, -, 1-9) Copyright Ó 2017 Association of Nurses in AIDS Care Key words: HIV, symptom burden, type 2 diabetes

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pproximately 10-15% of persons living with HIV (PLWH) have a comorbid diagnosis of diabetes mellitus (DM; Brown, Tassiopoulos, Bosch, Shikuma, & McComsey, 2010; Butt et al., 2009), making DM one of the most common comorbid conditions among PWLH (Goulet et al., 2007). Symptom burden has

been defined as the cumulative impact of symptom severity along with the patient’s perception of each symptom’s impact (Cleeland, 2007). HIV and DM are both long-term chronic conditions associated with high symptom burdens, and they share several symptoms, including neuropathy, fatigue, and sex problems (American Diabetes Association, 2015; Harding, Molloy, Easterbrook, Frame, & Higginson, 2006; Wilson et al., 2016; Zuniga, Nguyen, & Holstad, 2016). Symptoms associated with HIV are due, in part, to a combination of disease progression and side effects of antiretroviral therapy (Gay et al., 2011; Gonzalez et al., 2007) that include nausea, diarrhea, and fatigue (AIDSinfo, 2016; Kaplan et al., 2009). High HIV symptom burden has been associated with poor medication adherence, higher levels of depression, Julie Ann Zuniga, PhD, RN, is an Assistant Professor, School of Nursing, The University of Texas at Austin, Austin, Texas, USA. (*Correspondence to: jzuniga@nursing. utexas.edu). Eliezer Bose, PhD, AGACNP-BC, is an Assistant Professor, School of Nursing, The University of Texas at Austin, Austin, Texas, USA. Jungmin Park, PhD, RN, is an Assistant Professor, School of Nursing, California State University, Chico., California, USA. M. Danet LapizBluhm, PhD, RN, is an Associate Professor, School of Nursing, The University of Texas Health Science Center, San Antonio, San Antonio, Texas, USA. Alexandra A. Garcıa, PhD, RN, FAAN, is the Director of Community Engagement and Public Health, School of Medicine, and an Associate Professor, School of Nursing, The University of Texas at Austin, Austin, Texas, USA.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. -, No. -, -/- 2017, 1-9 http://dx.doi.org/10.1016/j.jana.2017.07.004 Copyright Ó 2017 Association of Nurses in AIDS Care

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lower quality of life, and advanced progression of the disease (Gay et al., 2011; Gonzalez et al., 2007). Similarly, symptom burden for persons with DM has been associated with poor quality of life, reduced medication adherence, worse depression, higher glycosylated hemoglobin, and higher body mass index (Papelbaum et al., 2010; Sacco et al., 2007). DM-related symptoms result from high or low blood glucose levels, side effects of medications, and long-term complications. High glucose levels, for example, cause diuresis when glucose levels exceed the kidneys’ threshold, which in turn leads to excessive thirst due to loss of fluid (Leslie, Lansang, Coppack, & Kennedy, 2012). Blurry vision results from increased glucose levels in the eye, which interferes with refraction. High glucose levels damage the vascular system and can lead to paresthesia (Abbott et al., 2002). Patients with DM have reported experiencing an average of five symptoms in the previous month, the most worrisome being blurry vision, headaches, pain, and excessive fatigue (Coffman & Norton, 2012; Garcıa, 2005; Sudore et al., 2012). Recently, using the HIV Symptom Index (HIVSI) to investigate HIV symptom patterns in PLWH (N 5 1,885), Wilson and colleagues (2016) identified two main symptom clusters, with two overlapping symptoms (fatigue and muscle aches/joint pain). Willard and colleagues (2009) reported that in adults with HIV, of the top 10 most prevalent symptoms reported by participants, 6 were also symptoms of hypoglycemia or hyperglycemia. Given the nature of HIV and DM, we postulated that the addition of DM would result in a different symptom pattern than that for HIV alone. The purpose of our study was to describe symptom patterns for persons living with HIV and DM (PLWH1DM).

Methods Study Design and Subjects Our study was a secondary analysis of data collected from the Center for AIDS Research Network of Integrated Clinical Systems (CNICS). CNICS data were collected from approximately 31,000 PLWH who visited one of eight clinics located at the University of Washington; Case Western Reserve University;

University of California, San Francisco; University of North Carolina at Chapel Hill; Johns Hopkins University; Fenway Health in Boston, Massachusetts; University of California, San Diego; and University of Alabama at Birmingham. During their clinical appointments, patients were asked to complete the HIVSI and provide other patient-reported outcomes such as adherence to HIV treatment and quality of life. For this study, we included data only from patients who were diagnosed with HIV and DM (N 5 951), treated at a CNICS clinic in 2015, prescribed antiretroviral therapy for more than 6 months, and older than 18 years of age. The study was considered exempt by the University of Texas at Austin Institutional Review Board because only de-identified data were included in the dataset. Instrument The HIVSI is a self-report 20-item instrument with five response choices: 0 5 I do not have this symptom; 1 5 I have this symptom, and it doesn’t bother me; 2 5 I have this symptom, and it bothers me a little; 3 5 I have this symptom, and it bothers me; and 4 5 I have this symptom, and it bothers me a lot (Justice et al., 2001). We computed a total score by tallying responses for all 20 symptoms to represent the concept of symptom burden. The 20 symptoms measured by the index are fatigue, fever, dizziness, neuropathy, forgetfulness, nausea, diarrhea, sadness, anxious/anxiety, poor sleep, skin problems, coughing, headache, poor appetite, bloating, aches, sex problems, change in body fat distribution, weight loss, and hair loss. Data Analysis All statistical analyses were conducted using the Statistical Package for the Social Sciences (IBM, Armonk, NY) version 24 and R version 3.3.2. For analysis of symptom prevalence, we considered only the first visit to clinics in 2015. We assessed for the presence of outliers, because outliers can lead to a misinterpretation of findings (Penny, 1996). We examined the internal structure of the HIVSI data using principle components analysis (PCA) to discover patterns of relationships between the reported symptoms (Nunnally & Bernstein, 1994).

Zuniga et al. / Diabetes Changes Symptoms Cluster Patterns in Persons Living With HIV

Item distributions and preliminary analyses. We examined the responses for each of the 20 HIVSI items for each patient and the overall prevalence of occurrence in the total sample. Next, we confirmed that the sample was an adequate size using Tabachnick’s guidelines that stated that 300 cases were necessary to perform PCA (Tabachnick & Fidell, 2007). The classic Kaiser-Myer-Olkin (KMO) statistic was computed to examine variance among the items and establish the appropriateness of performing the PCA (Bartlett, 1950; Kaiser, 1974). According to the Kaiser criterion, the KMO index ranges from 0 to 1, with .5 and above considered suitable for PCA; a KMO of less than .5 would render the data unsuitable. We computed a correlation matrix to investigate the interrelationships between individual symptom items and to identify possible clusters of items. Generally, correlation coefficients greater than .3 have been used to identify item patterns, although items with correlations higher than .8 might be redundant and were inspected further (Tabachnick & Fidell, 2007). Principal component analysis. The PCA method is used to collapse a large amount of information into categories or components and is ideal for identifying clusters of symptoms that occur together. We used PCA of the HIVSI total scores to identify the fewest number of unrelated variables, or components, that explained the variance in the symptom items and included a combination of the items’ unique and shared variance (Costello & Osborne, 2005). Because symptoms in the HIVSI are correlated with each other to some extent, we used an oblique rotation (Promax) that allowed us to examine how much the items were inter-correlated and to make the pattern of the factor loadings, or the correlations of the symptom items with the composite component or variable, clearer. The PCA was performed by extracting components with eigenvalues greater than 1, meaning that a component was dropped unless it extracted at least as much variance as the equivalent of one original item, per the Kaiser criterion (Nunnally & Bernstein, 1994). A Cattell scree plot produced a visual representation of the components that accounted for the most variance to make identification of the largest components easier. Based on the Promax rotation, we selected items with component loadings greater than .32 to form subscales (Tabachnick &

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Fidell, 2007). Items with loadings higher than .32 on more than one component were considered cross-loaders, and we examined the conceptual meaning of those items to determine their best factor assignment. Once subscales were confirmed, we created labels for the subscale based on the prominent pathophysiological mechanisms of the symptoms in the subscale (Tabachnick & Fidell, 2007). Then we assessed the internal consistency of the symptom clusters composed of symptoms with fair factor loadings using Cronbach’s alpha.

Results Sample Characteristics In total, 951 people with confirmed dual diagnoses of HIV and DM composed the sample (see Table 1). Most were men (79.8%) and White (32.2%); the mean age was 55.6 years (69.12). The most prevalent symptoms (see Table 2) were fatigue (57.5%), poor sleep (52.4%), aches (52.4%), neuropathy (49.1%), and sadness (49.3%). Of all the symptoms, those rated most bothersome were aches (18.1%), neuropathy (17.1%), poor sleep (16.0%), body image (12.9%), and sex problems (12.0%). PLWH1DM Symptom Clusters Analysis The HIVSI met all assumptions for PCA analyses. PCA analyses revealed three symptom clusters (see Figure 1 and Table 3). Seven of 20 symptoms loaded on Factor 1 and accounted for 40.16% of the total Table 1.

Characteristics of Patients With DM1HIV (N 5 951)

Participant Characteristics Present gender Male Female Race/ethnicity White White-Hispanic African American Other Note. DM 5 diabetes mellitus.

Frequency (%) 759 (79.8) 192 (20.2) 411 (32.2) 118 (12.4) 347 (36.5) 75 (18.9)

4 JANAC Vol. -, No. -, -/- 2017 Table 2.

Symptom Prevalence and Distress in PLWH1DM Compared to PLWH

Most Prevalent Symptoms

Prevalence of Symptom Present %

Fatigue Nausea Diarrhea Headache Loss of appetite Coughing Dizzy Fever Bloating Memory loss Sadness Sex problems Neuropathy Muscle ache Poor sleep

58 58 57 57 57 56 56 56 55 55 55 55 54 53 53

HIV1DM, Zuniga et al. Prevalence of Prevalence of Symptom Symptom Bothers a Lot % Bothersome % 65 35 30 34 35 35 38 32 33 36 34 28 27 29 31

30 8 13 9 8 9 7 12 12 9 11 17 19 18 16

Prevalence of Symptom Present % 47 21 24 36 24 28 25 27 25 35 40 28 36 48 51

PLWH, Wilson et al. Prevalence of Prevalence of Symptom Symptom Bothers a Lot % Bothersome % 84 72 71 75 74 74 76 79 83 73 77 80 82 82 82

31 28 28 28 31 27 19 24 29 20 25 38 40 35 35

Note. DM 5 diabetes mellitus. Response range is 0-4; 0 5 I do not have this symptom; 1 5 I have this symptom, and it doesn’t bother me; 2 5 I have this symptom, and it bothers me a little; 3 5 I have this symptom, and it bothers me; 4 5 I have this symptom, and it bothers me a lot. Column B represents that the symptom is bothersome at a score of 2 to 3.

variability in the 20 symptoms. The seven symptoms loaded on factor 2 accounted for 3.4% of the variability, and the three symptoms loaded on factor 3 accounted for 2.4% of the total variability. None of the symptoms in the three clusters overlapped between clusters. Symptom Cluster 1 comprised the following symptoms: sadness, anxious, poor sleep, fatigue, forgetful, sex problems, change in body fat distribution, neuropathy, and aches (n 5 7). The most prevalent symptoms in this cluster were sadness, anxious, poor sleep, and fatigue (see Figure 1). Symptom Cluster 2 comprised nausea, dizziness, poor appetite, fever, cough, bloating, headache, and diarrhea (n 5 6). The most prevalent symptoms in Cluster 2 were nausea, dizziness, and poor appetite. Symptom Cluster 3 consisted of weight loss, hair loss, and skin problems (n 5 3). Clusters 1 and 2 are highly internally consistent (Cronbach’s a 5 .894 and .835, respectively), meaning if respondents reported one symptom in the cluster, they were likely to report another in the same cluster. Cluster 3 was less internally consistent (Cronbach’s a 5 .594).

Discussion PCA for PLWH1DM resulted in three distinct symptom clusters. Cluster 1 included mostly the psychological and neurological symptoms (sadness, anxious, forgetful, neuropathy), whereas Cluster 2 included gastrointestinal and flu-like symptoms (nausea, poor appetite, diarrhea, fever, and headache). Cluster 3 was composed of symptoms associated with physical changes in body appearance (weight loss, hair loss, and skin problems). Symptoms commonly associated with DM were grouped mostly into Cluster 1: neuropathy, anxiety, and sex problems. However, the most common DM symptoms, such as blurry vision, polyuria, and polydipsia, were not captured by the HIVSI. Therefore, PWLH1DM may experience even more symptoms than those presented here. In comparison with Wilson and colleagues’ (2016) study of symptom burden in PLWH, which drew participants from only one of the CNICS sites and also used the HIVSI, our study demonstrated a different pattern in prevalence and bothersomeness (see Table 2). All of the symptoms were reported by

Zuniga et al. / Diabetes Changes Symptoms Cluster Patterns in Persons Living With HIV

Factor Analysis sadness anxious

0.8

no sleep

0.8 0.8

fatigue

0.7

forgetful

0.6

MR1

0.5

sex problems

0.5 bodyfat

0.5

neuropathy

0.8

0.4

aches nausea

0.7 MR2

0.4

0.7

dizzy poor appetite

0.6 0.5

fever

0.5

cough

0.5

0.4

0.5

bloating

0.4 MR3

headache diarrhea 0.5 weight loss

0.3 0.3

hair loss skin problems

Note. MR = Minimal Residual

Figure 1. Principal component analysis for HIV symptoms. MR 5 minimal residual.

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6 JANAC Vol. -, No. -, -/- 2017 Table 3.

Summary of Items and Factor Loading for Three-Factor Solution of HIV Symptom Index (N 5 951)

Symptom Fatigue Sadness Anxious Poor sleep Forgetful Neuropathy Aches Dizzy Nausea Decreased appetite Bloating Cough Headache Fever Weight loss Change in body fat distribution Skin problems Diarrhea Sex problems Hair loss

Factor Loading 1 2 3 0.700a 0.694a 0.680a 0.679a 0.585a 0.523a 0.490a 0.395 0.229 0.239 0.33 0.283 0.35 0.161 0.084 0.448 0.265 0.347 0.441 0.229

0.359 0.293 0.317 0.286 0.34 0.354 0.342 0.615a 0.612a 0.531a 0.473a 0.465a 0.458a 0.45a 0.227 0.092 0.247 0.401 0.125 0.179

.190 0.270 0.220 0.180 0.25 0.246 0.325 0.269 0.269 0.377 0.442 0.345 0.223 0.073 0.557a 0.486a 0.455a 0.313 0.350 0.440

a. Highest factor loading.

more than half of the sample with HIV1DM, whereas in the Wilson and colleagues (2016) study of PLWH, poor sleep was the only symptom reported by more than 50% of the sample. Our PLWH1DM group had higher prevalence but reported being much less bothered by symptoms than PLWH in the Wilson and colleagues (2016) study. These findings were consistent with a previous study of Mexican Americans with DM (Garcıa, 2005), where there was a high prevalence of symptoms, but the symptoms were rated low seriousness. The pattern of high prevalence but low seriousness may be due to the need of the participants to ignore discomfort in order to focus on family and work obligations or that patients normalized the symptoms, for instance, attributing them to normal aging patterns regardless of disease control (Siegel, Schrimshaw, & Dean, 1999; Willard et al., 2009). In our study, people reported a much higher prevalence of neuropathy (54.6%) than previous studies of PLWH, which reported a prevalence of approximately 30% (Evans et al., 2011; Willard et al., 2009; Wilson et al., 2016). A higher prevalence of

Table 4.

Comparison of Causes of Most Common Symptoms of HIV and Diabetes

Symptoms Anxious Bloating Blurred vision Change in body fat distribution Confused Coughing Sex problems Diarrhea Dizzy Fatigue Fever Frequent urination Hair loss Headache Hungry Increased thirst Loss of appetite Memory loss Muscle ache Nausea Neuropathy Poor sleep Sadness Shaky Skin problem Sweaty Weight loss

HIV

Hypoglycemia

X X

X X

Hyperglycemia

X

X X X X X X X X

X X X X

X X

X X

X X

X X X X X X X

X

X X X X

X

neuropathy in persons with DM was to be expected due to microvascular damage caused by high glucose levels. Davies, Brophy, Williams, and Taylor (2006) studied prevalence and severity of neuropathy in persons with DM but not HIV (N 5 326; mean age 67 6 11.5 years) and found that only 26.4% of participants reported no neuropathic pain. Neuropathy is a symptom of the progression of diabetes, which might be relieved or prevented by keeping blood glucose within recommended ranges (Poncelet, 2003). In addition, we found higher rates of depression in our PLWH1DM than Wilson and colleagues (2016) found in PLWH only. Differences in symptom patterns between the two samples could be partially explained by the difference in ages. The Wilson and colleagues (2016) sample of PLWH had a mean age of 44 years, whereas our sample’s mean age was 55 years, which is consistent with a higher incidence and prevalence of DM as the population ages. However, McGowan

Zuniga et al. / Diabetes Changes Symptoms Cluster Patterns in Persons Living With HIV

and colleagues (2014) reported that some symptoms, such as depression, decreased as PLWH aged, so we would expect a lower prevalence in our study. Several studies have documented a higher prevalence of depression in people with DM, compared to the general population. For example, Ali, Stone, Peters, Davies, and Khunti (2006) reported that the prevalence of depression in persons with diabetes was approximately 17.6%, which was higher than in the general population (9.8%). Therefore, the higher rate of depression documented in our study could reflect the stress of managing two chronic illnesses, changes in physiology experienced by PLWH1DM, or a synergistic effect of the comorbid conditions. Depression and neuropathy are only two symptoms of HIV that are also common DM symptoms (see Table 4; American Diabetes Association, 2015; Garcıa, 2005; Justice et al., 2001). Eight symptoms are associated with both chronic illnesses. For example, headache could be associated with HIV, hypoglycemia, hyperglycemia, or an unrelated condition. This overlap may cause patients to be confused about how to treat symptoms; they may not know which action is appropriate to relieve symptoms. Health care providers can encourage patients to check their blood glucose even when the symptom is not only related to glucose levels. The symptom clusters generated for PLWH1DM also differed from the Wilson and colleagues (2016) analysis. Wilson and colleagues (2016) documented two clusters, but our analyses produced three symptom clusters, and the symptoms in each cluster differed. Symptoms that clustered into the Wilson and colleagues (2016) Cluster 2, which accounted for 7% of the variance, were subsumed into Cluster 1 in our study, which accounted for 40% of the variance. Wilson’s Cluster 1 accounted for 41% of the variance. It could be that there was a limit to the amount of a variance that could be accounted for by symptoms in this scale or that a difference could also be accounted for by the difference in prevalence in symptoms between the two groups. Limitations Strengths of our study include the power of the statistical analysis and the fact that data were obtained from participants at several academic clinics across

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the country. However, we did not control for patient medication usage or other medical conditions, which might have affected symptom prevalence.

Conclusions PLWH1DM reported a high prevalence of symptom burden with low levels of burdensomeness that clustered into three groups. These findings were different from a previous study that used the same instrument; both studies were part of the CNICS cohort. The differences reported could be attributed to an older sample or to a synergistic effect of the comorbid conditions. Clinicians should comprehensively assess symptoms common to multiple comorbid conditions. In particular, clinicians should assess for depression and neuropathy in patients with PLWH1DM and encourage tight control of glucose to help relieve some symptoms. Future research should replicate our study using a diabetes symptoms burden instrument, and compare those outcomes to the diabetes population. If symptom clusters vary greatly, it may be necessary to create an instrument that incorporates symptoms from both conditions in order to better understand PLWH1DM’s symptom burden.

Disclosures The authors report no real or perceived vested interests that relate to this article that could be construed as a conflict of interest.

Key Considerations  Patients living with a dual diagnosis of HIVand diabetes have high symptom burdens; almost half reported symptoms of depression and neuropathy.  HIV symptom patterns changed for patients with an additional diagnosis of diabetes.  Nurses can help people living with HIV infection identify symptoms that may also be symptoms of hyperglycemia or hypoglycemia.

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Acknowledgments Data set for this study was provided by the Center for AIDS research (CFAR) Network of Integrated Clinical Systems (CNICS), a National Institutes of Health-funded program (R24 AI067039) made possible by the National Institute of Allergy and Infectious Diseases and the National Heart, Lung, and Blood Institute. The CFAR sites involved in CNICS include the University of Alabama at Birmingham (P30 AI027767); University of Washington (P30 AI027757); University of California, San Diego (P30 AI036214); University of California, San Francisco (P30 AI027763); Case Western Reserve University (P30 AI036219); Johns Hopkins University (P30 AI094189, U01 DA036935); Fenway Health/Harvard (P30 AI060354); and the University of North Carolina at Chapel Hill (P30 AI50410). Editorial support with manuscript development was provided by the Cain Center for Nursing Research and the Center for Transdisciplinary Collaborative Research in SelfManagement Science (P30, NR015335) at The University of Texas at Austin School of Nursing.

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