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Cardiovascular disease risk among transgender women living with HIV in the United States
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PLOS ONE Published: July 20, 2020
Bennett J. Gosiker1, Catherine R. Lesko1, Ashleigh J. Rich2, Heidi M. Crane3, Mari M. Kitahata3, Sari L. ReisnerI4,5,6,7, Kenneth H. Mayer4,8, Rob J. Fredericksen3, Geetanjali Chander9, William C. MathewsI10, Tonia C. PoteatI11*
1 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States of America, 2 School of Population and Public Health, Faculty of Medicince, University of British Columbia, Vancouver, BC, Canada, 3 Department of Medicine, Division of Allergy and Infectious Diseases, University of Washington, Seattle, WA, United States of America, 4 The Fenway Institute, Boston, MA, United States of America, 5 Division of General Pediatrics, Boston Children’s Hospital, Boston, MA, United States of America, 6 Department of Pediatrics, Harvard Medical School, Boston, MA, United States of America, 7 Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, United States of America, 8 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States of America, 9 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States of America, 10 School of Medicine, University of California San Diego, San Diego, CA, United States of America, 11 Department of Social Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America
Our analysis presents unique findings that establish a baseline for exploring CVD risk among TW living with HIV. CVD among people living with HIV and particularly among TW living with HIV is a growing concern. Key contributors to CVD risk unique to TW living with HIV-such as GAHT, stress and stigma, viral inflammation, and cumulative ART exposure-are not captured by the PCE and FRS. Future investigations of CVD risk among TW living with HIV should collect data on intermediate CVD outcomes (e.g. coronary artery calcium, carotid artery intima-media thickness) or CVD endpoints (e.g. myocardial infarction, stroke) so that actual (versus predicted) CVD morbidity in TW can be quantified.
The variation in CVD risk estimates based on the operationalization of “sex” highlights the practical limitations of both the FRS and PCE when used by clinicians who seek to identify and address elevated CVD risk among their TW patients with HIV. It is unclear if the differences in CVD risk found between CW and CM can be attributed to hormonal differences alone or if other sex and/or gender-based factors account for this differences. Therefore, important research questions remain on which “sex” is appropriate to input when attempting to estimate CVD risk among TW via these commonly used calculators.
In this study, predicted CVD risk for TW was not appreciably higher than for CM. However, CVD risk as quantified by the PCE risk score and FRS do not capture the potential effects of CVD risk factors unique to TW including but not limited to exogenous sex hormone use and stress related to violence or stigma. Exogenous estrogen use affects inflammation and immune function [2, 9, 12, 14, 16, 19, 22] as does stress [42-45]. Our results should be interpreted cautiously given the absence of CVD endpoints and the notable affect of altering how we operationalized the “sex” variable for TW in the CVD risk equations.
Abstract
Background
Transgender women (TW) are disproportionately affected by both HIV and cardiovascular disease (CVD).
Objectives
We aim to quantify prevalence of elevated predicted CVD risk for TW compared to cisgender women (CW) and cisgender men (CM) in HIV care and describe the impact of multiple operationalizations of CVD risk score calculations for TW.
Design
We conducted a cross-sectional analysis of patients engaged in HIV care between October 2014 and February 2018.
Setting
The Centers for AIDS Research Network of Integrated Clinical Systems, a collaboration of 8 HIV clinical sites in the United States contributed data for this analysis.
Patients
221 TW, 2983 CW, and 13467 CM.
Measurements
The measure of interest is prevalence of elevated 10-year cardiovascular disease risk based on ACC/AHA Pooled Cohort Risk Assessment equations (PCE) and the Framingham Risk Score (FRS), calculated for TW by: birth-assigned sex (male); history of exogenous sex hormone use (female/male); and current gender (female).
Results
Using birth-assigned sex, the adjusted prevalence ratio (aPR) was 2.52 (95% CI: 1.08,5.86) and 2.58 (95% CI: 1.71,3.89) comparing TW to CW, by PCE and FRS, respectively. It was 1.25 (95% CI: 0.54,2.87) and 1.25 (95% CI: 0.84,1.86) comparing TW to CM, by PCE and FRS, respectively. If TW were classified according to current gender versus birth-assigned sex, their predicted CVD risk scores were lower.
Limitations
PCE and FRS have not been validated in TW with HIV. Few adjudicated CVD events in the data set precluded analyses based on clinical outcomes.
Conclusions
After adjustment for demographics and history of HIV care, prevalence of elevated CVD risk in TW was similar to CM and equal to or higher than in CW, depending operationalization of the sex variable. Future studies with CVD outcomes are needed to help clinicians accurately estimate CVD risk among TW with HIV.
Discussion
This study used the FRS and PCE to estimate the prevalence of elevated predicted CVD risk for TW compared to CW and CM in HIV care and described the impact of multiple operationalizations of sex in CVD risk score calculations for TW. After adjustment for demographics and history of HIV care, prevalence of elevated CVD risk in TW was similar to CM and equal to or higher than in CW, depending operationalization of the sex variable. Adjusted estimates were meaningfully different from crude estimates for some estimated prevalence ratios, particularly when using current gender for the PCE. That is, although in adjusted analyses TW had elevated predicted risk of CVD compared to CW, their crude predicted risk of CVD was lower in almost all instances, likely as a function of their younger age and lower prevalence of diabetes (Table 2).
Estimated 10-year CVD risk was highest for TW when classifying them according to birth-assigned sex (male) and lowest when classifying them according to current gender (female). This is not surprising because both the PCE and FRS attribute greater risk to persons classified as male [27, 28]. The sample average risk scores for TW was between these two extremes when calculated based on exogenous sex hormone use. After adjustment, TW had a prevalence of elevated CVD risk comparable to CM. TW consistently had an equivalent or higher prevalence of elevated CVD risk compared to in CW in adjusted analyses.
One of the only other existing studies exploring CVD among TW (n = 23) and CM (n = 92) living with HIV found elevated levels of anemia, depression, HCV infection, and poor HIV control [35]. Many of the traditional CVD risk factors measured in the study were not different among TW and CM. Our larger sample of TW (n = 221) had a lower prevalence of viral suppression and diabetes, lower CD4 counts, and higher prevalence of treated hypertension than CW and CM (Table 2, Table 3).
In one study of TW (N = 214) and age-matched CM and CW without HIV in Belgium, TW had 4.2% higher prevalence of prior MI than CM, and 18.7% higher prevalence of prior MI than CW. TW also had higher prevalence of history of stroke or cerebrovascular disease, obesity, and diabetes (4.2% versus 0.6% in CM and 1.5% in CW) [11]. The largest difference in prevalence of a CVD risk factor in our sample was treatment for hypertension; 73% of TW had a history of treatment for hypertension compared with 40% of CM and 55% of CW. The differences in the prevalence of CVD risk factors in our study sample and the sample from Belgium may reflect differences in cultural norms related to CVD risk factors and gender, the influence of HIV, or socioeconomic factors that intersect with the HIV epidemic.
We found no other publishd studies that assessed cardiovascular disease risk or events among TW living with HIV and accounted for GAHT use. Studies of the effect of GAHT use on CVD risk among TW without HIV have varying results, with some evidence of increases in thromboembolic events [36, 37]. Among patients who received care in the Kaiser Permanente health care system in Georgia or California, the adjusted hazard ratio of venous thromboembolism in TW using exogenous sex hormones was 3.2 (95% CI: 1.5,6.5) compared to CM and 2.5 (95% CI: 1.2-5.0) compared to CW. Incidence of ischemic stroke and MI were similar across comparison grops [38]. Neither the PCE nor FRS were designed to capture risk for thromboembolic events [27, 28]. Other studies have shown elevated endothelial activation, inflammatory biomarkers, and brachial artery diameter as indicators of elevated CVD risk among TW [39-41].
In this study, predicted CVD risk for TW was not appreciably higher than for CM. However, CVD risk as quantified by the PCE risk score and FRS do not capture the potential effects of CVD risk factors unique to TW including but not limited to exogenous sex hormone use and stress related to violence or stigma. Exogenous estrogen use affects inflammation and immune function [2, 9, 12, 14, 16, 19, 22] as does stress [42-45]. Our results should be interpreted cautiously given the absence of CVD endpoints and the notable affect of altering how we operationalized the “sex” variable for TW in the CVD risk equations.
The variation in CVD risk estimates based on the operationalization of “sex” highlights the practical limitations of both the FRS and PCE when used by clinicians who seek to identify and address elevated CVD risk among their TW patients with HIV. It is unclear if the differences in CVD risk found between CW and CM can be attributed to hormonal differences alone or if other sex and/or gender-based factors account for this differences. Therefore, important research questions remain on which “sex” is appropriate to input when attempting to estimate CVD risk among TW via these commonly used calculators.
Importantly, neither the FRS nor PCE have been validated among TW, and the correspondence between predicted risk and actual risk is unknown for this population. The PCE and FRS are useful tools for motivating discussions of CVD prevention for people living with HIV, but were originally developed and calibrated for use in the general population. Persistent immune activation in people living with HIV and increased systemic inflammation is thought to contribute to elevated risk for a variety of cardiovascular disease outcomes [23]. Feinstein et al. assessed the PCE risk score calculation in CNICS and found the best fit for white men, but under-prediction for Black men, Black women, and white women [24]. The proportion of Black participants in this study varied by gender, making up 34%, 66%, and 45% of CM, CW, and TW, respectively (Table 2). These findings may have implications for PCE risk scores calculated in this analysis given the racial differences by gender. Attempts to incorporate HIV-related metrics (e.g. viral load, CD4) have not yielded any additional fit beyond that provided by the current PCE [24]. A better calibrated tool has yet to be validated in people living with HIV, so the PCE and FRS remain the best available tool for exploring CVD risk.
CNICS is one of the largest clinical cohorts of people living with HIV and to our knowledge, this analysis including 221 TW is the largest cohort study to assess CVD risk and GAHT use among TW living with HIV to date. Yet, since the beginning of follow-up in this cohort (as far back as 1995 for some CNICS sites) there have only been 3 adjudicated myocardial infarctions documented among TW participants. This low incidence of myocardial infarctions could be explained by the younger age of TW compared with CW and CM in the CNICS cohort. Given the limited number of CVD events, this analysis considering multiple predictors of CVD (systolic blood pressure, diabetes, hypertension, cholesterol and smoking) together using the PCE and FRS represents an important first step toward describing the cardiovascular health of TW living with HIV.
Medications captured by CNICS are prescriptions, and may not reflect true medication use. Furthermore, for patients who received care elsewhere prior to enrolling in HIV care in a CNICS clinic, and for patients who receive primary medical care from someone other than their HIV provider, some medications may be missing from the medical record. This may mean that we underestimated years of ART exposure or prior exposure to an abacavir-containing ART regimen. However, history of ART exposure is such an important piece of information when providers decide on future ART regimens that we expect measurement error in these two variables to be minimal. Medication use that is not prescribed, e.g., sex hormones obtained outside of the formal health sector, is not likely to be recorded. Our sample of TW was not powered to stratify by GAHT regimen, dose, or years of exposure, preventing determination of any differential CVD risk by these factors. Further research accounting for these prescription details are a crucial next step in chatacterizing the effects of GAHT on CVD risk.
The ability to identify TW within CNICS allows for more in depth clinical insight than prior studies of CVD among TW living with HIV. Our use of both CW and CM with HIV as control groups allows us to account for variability in sex as well as traditional CVD risk factors. This is even more useful given findings that suggest CM with HIV have higher risk of CVD compared to CW with HIV [46]. The use of multiple imputation with chained equations in this analysis allows for calculation of PCE risk scores and FRS for all participants. This is particularly helpful given the lower number (N = 221) of TW within the study.
Our analysis presents unique findings that establish a baseline for exploring CVD risk among TW living with HIV. CVD among people living with HIV and particularly among TW living with HIV is a growing concern. Key contributors to CVD risk unique to TW living with HIV-such as GAHT, stress and stigma, viral inflammation, and cumulative ART exposure-are not captured by the PCE and FRS. Future investigations of CVD risk among TW living with HIV should collect data on intermediate CVD outcomes (e.g. coronary artery calcium, carotid artery intima-media thickness) or CVD endpoints (e.g. myocardial infarction, stroke) so that actual (versus predicted) CVD morbidity in TW can be quantified.
Introduction
Transgender women (TW) are disproportionately affected by HIV infection and related comorbidities [1-4]. Globally, 19% of TW are living with HIV and TW have 49 times greater odds of HIV-infection compared to cisgender adults of reproductive age in their respective countries [5]. In the United States, the most recent HIV prevalence estimate among TW is 14% [1] compared with 0.3% in the general population [6].
People living with HIV have a higher prevalence of cardiovascular disease (CVD) than persons without HIV, related to both higher prevalence of traditional risk behaviors for CVD such as smoking [7, 8], and the effects of HIV itself [9, 10]. HIV infection is associated with chronic inflammation and elevated burden of CVD risk factors such as diabetes [11]. Specific antiretroviral therapy (ART) regimens have also been associated with higher risk of CVD [12, 13].
In the general population, TW experience disparities in prevalence of CVD risk factors, rates of events (e.g., myocardial infarction, stroke, venous thromboembolism) [7, 8, 11], and potentially risk of CVD-related mortality [14, 15] compared to their cisgender counterparts. This elevated CVD burden is a function of multilevel factors, including biological (e.g., exogenous sex-hormone use), interpersonal (e.g., gender-based stigma) and socio-structural (e.g., discrimination) [3, 14-16].
TW living with HIV are uniquely vulnerable to CVD morbidity as a result of potentially mutually-reinforcing HIV-related and gender-identity-related risks. For example, gender-related stigma contributes to sub-optimal: retention in care [15], ART adherence, and viral suppression for TW living with HIV [17], all factors that may impact CVD risk. Gender affirming hormone therapy (GAHT), including exogenous sex-hormone use, is an important part of healthcare for many TW [18-20]. GAHT can increase ART adherence and viral suppression for TW living with HIV [18-20] which may improve outcomes [21]. However, exogenous estrogen use affects inflammation and immune function, potentially conferring increased CVD risk among TW using GAHT [2, 9, 12, 14, 16, 19, 22]. In short, both HIV and GAHT play a role in CVD [23, 24].
Despite the unique vulnerability to CVD-related morbidity and mortality faced by TW living with HIV, data on CVD risk among TW living with HIV are lacking [14]. The objectives of this study were to quantify elevated CVD risk prevalence for TW compared to cisgender women (CW) and cisgender men (CM) engaged in HIV care and describe the impact of multiple operationalizations of CVD risk scores for TW.
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