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CV Risk Factors Common Among 50 Yr Old PLWH -
"Cardiovascular Risk and Health Among People
With Human Immunodeficiency Virus (HIV) Eligible
for Primary Prevention: Insights From the REPRIEVE Trial"
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Pamela S. Douglas,1, Triin Umbleja,2 Gerald S. Bloomfield,1 Carl J. Fichtenbaum,3 Markella V. Zanni,4 Edgar T. Overton,5 Kathleen V. Fitch,4 Emma M. Kileel,4 Judith A. Aberg,6 Judith Currier,7 Craig A. Sponseller,8 Kathleen Melbourne,9 Anchalee Avihingsanon,10 Flavio Bustorff,11 Vicente Estrada,12 Kiat Ruxrungtham,10 Maria Saumoy,13 Ann Marie Navar,14 Udo Hoffmann,4 Heather J. Ribaudo,2 and Steven Grinspoon4; on behalf of the REPRIEVE Investigators
median age of 50 years
Poor CV health by LS7 was common among REPRIEVE participants, regardless of PCE.This suggests a critical and independent role for lifestyle interventions in conjunction with conventional treatment to improve CV outcomes in PWH. Thirty-six percent (34% of women; 37% of men) met ideal targets in ≤2 components, considered poor CV health.
In addition to traditional risk factors and scores, the American Heart Association recommends evaluating Life's Simple 7 (LS7) as a novel, comprehensive measure of CV health, both to characterize populations and to guide interventions [12]. LS7 was conceived as more actionable given its inclusion of 4 health behaviors-smoking, diet, physical activity, and body mass index (BMI)-and 3 health factors-blood pressure, total cholesterol, and glucose-with defined goals for improvement. Furthermore, LS7 is closely associated with CV outcomes in multiple cohorts [13]. However, to our knowledge, it has not been applied in a population of PWH.
Risk Factors
CV risk factors were common, with 50% being current or former smokers, 19% having a family history of premature CVD, 36% being hypertensive, a median BMI of 25.9 kg/m2, and 29% having a history of treatment for depression (Table 1). Trial entry criteria limited enrollment of people with diabetes to those with very low LDL cholesterol [14]. The overall median PCE risk score was 4.5% (Q1, Q3: 2.2, 7.2), with the proportion of participants decreasing from 29% in the lowest PCE risk category (<2.5%) to 9% in the highest category (>10%); 78% had a PCE risk score <7.5%. As expected, the prevalence of factors used to compute the PCE score increased across increasing PCE risk categories, including age, sex, smoking, diabetes, race, and elevated blood pressure. There were limited increases in LDL cholesterol across PCE risk categories, as expected based on trial entry criteria.
As survival with HIV has improved, the relative impact of cardiovascular disease (CVD) has increased [6]. As a result, CVD is an important, potentially modifiable cause of morbidity and mortality [9] and an important challenge [10]. Although HIV is recognized in current guidelines [11] as a "risk enhancer" using the American College of Cardiology/American Heart Association Pooled Cohort Equations (PCE), optimal strategies for primary prevention in PWH remain unknown.
In addition to traditional risk factors and scores, the American Heart Association recommends evaluating Life's Simple 7 (LS7) as a novel, comprehensive measure of CV health, both to characterize populations and to guide interventions [12]. LS7 was conceived as more actionable given its inclusion of 4 health behaviors-smoking, diet, physical activity, and body mass index (BMI)-and 3 health factors-blood pressure, total cholesterol, and glucose-with defined goals for improvement. Furthermore, LS7 is closely associated with CV outcomes in multiple cohorts [13]. However, to our knowledge, it has not been applied in a population of PWH.
As expected, those characteristics common to LS7 and PCE showed progressive worsening with increasing risk category; however, the others did not. Thus, LS7 complements the PCE risk score for overall assessments of CV status and underscores its possible utility as a tool for guiding CV health improvement. Specifically, even among those with lowest PCE risk, there were many participants with poor diet, elevated BMI, and low physical activity. It is likely that CV health is poorer among the higher CVD risk PWH population not included in this trial. Our findings are congruent with previous data in a small cohort study showing PWH to be substantially more sedentary than demographically matched HIV-negative controls, although differences in healthy diet were not significant [30]. Ongoing research in this area is expected to shed more light on these modifiable components of CV health [31].
Lower nadir CD4 was associated with increased PCE risk score, suggesting that degree of initial immune dysfunction relates to traditional longer-term risk indices. These findings are consistent with current theories, supported by associations between coronary plaque and arterial inflammation in HIV [24, 25], that increased inflammation and immune activation may contribute to excess CVD risk in PWH [24-26]. The degree and directionality of these effects extends our knowledge of the potential biological impact of immunological dysfunction on risk in PWH and suggests that immunological effects may be reflected in the components of the PCE score, despite its lack of any HIV-specific elements.
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Clinical Infectious Diseases, 16 June 2021
Life's Simple 7
The population median LS7 score (out of an ideal score of 14) was 9 (Q1, Q3: 7, 10; Figure 3). Ten percent had overall ideal CV health (≥5/7 ideal components) including 24 participants (0.3%) with 7/7 ideal components, 2% with 6 out of 7, and 8% with 5 out of 7 ideal components. Table 2 shows distribution of overall CV health by demographics and select characteristics. Thirty-six percent (34% of women; 37% of men) met ideal targets in ≤2 components, considered poor CV health. LS7 distributions were similar by sex, age, most HIV characteristics, and ART use. Asians and those in low SDI regions had a higher proportion with overall ideal CV health, largely driven by lower BMI and less smoking (Supplementary Figure 3). Note that the majority of Asians were enrolled from low and middle SDI countries.
CV risk factors were common, with 50% being current or former smokers, 19% having a family history of premature CVD, 36% being hypertensive, a median BMI of 25.9 kg/m2, and 29% having a history of treatment for depression (Table 1).
Comparison of HIV characteristics by PCE risk category showed some trends in ART duration and clinical immunologic parameters. For example, lower nadir CD4 was associated with increased PCE risk score but was attenuated when stratified by sex, race, and age (Supplementary Figure 2). In models adjusted for sex, race, age, and enrollment period, longer ART duration, entry ART regimen, lower nadir CD4, and higher entry CD4 were each associated with higher PCE risk score.
INTRODUCTION
Among 7382 REPRIEVE trial participants, the 10-year PCE-predicted CV risk score tracked well with demographics and other CV risk factors but was related less strongly to HIV characteristics or specific ART use. Ideal CV health was rare regardless of PCE risk score. Moreover, the PCE risk score did not capture common unhealthy behaviors, including poor diet, high BMI, and low physical activity. Our findings strongly suggest that key health behaviors should be assessed, in addition to standard risk, to better understand CV health in PWH. Furthermore, lifestyle interventions may be indicated regardless of CV risk estimate and/or conventional treatment. Ultimately, it will be important to assess how well the PCE and lifestyle-based behavior assessment algorithms can predict CVD risk over time in REPRIEVE and to determine the optimal risk/health stratification system in this population.
Persons with human immunodeficiency virus (HIV, PWH) are at increased risk for major adverse cardiovascular (CV) events, including myocardial infarction, heart failure, stroke, pulmonary hypertension, and sudden cardiac death [1-4], even after controlling for known risk factors. The associations between HIV and CV events are multifactorial and include inflammation and immune function changes related to chronic infection as well as metabolic dysregulation associated with HIV [2, 3, 5]. Furthermore, HIV is associated with adverse social determinants of health, with attendant increases in CV risk [6, 7]. Finally, both uncontrolled viremia and antiretroviral therapy (ART) can adversely affect CV risk factors and may increase CV risk [8].
As survival with HIV has improved, the relative impact of cardiovascular disease (CVD) has increased [6]. As a result, CVD is an important, potentially modifiable cause of morbidity and mortality [9] and an important challenge [10]. Although HIV is recognized in current guidelines [11] as a "risk enhancer" using the American College of Cardiology/American Heart Association Pooled Cohort Equations (PCE), optimal strategies for primary prevention in PWH remain unknown.
In addition to traditional risk factors and scores, the American Heart Association recommends evaluating Life's Simple 7 (LS7) as a novel, comprehensive measure of CV health, both to characterize populations and to guide interventions [12]. LS7 was conceived as more actionable given its inclusion of 4 health behaviors-smoking, diet, physical activity, and body mass index (BMI)-and 3 health factors-blood pressure, total cholesterol, and glucose-with defined goals for improvement. Furthermore, LS7 is closely associated with CV outcomes in multiple cohorts [13]. However, to our knowledge, it has not been applied in a population of PWH.
The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) is the largest long-term randomized trial to assess statin therapy as a primary CVD prevention strategy among PWH [14]. Using baseline data from trial participants enrolled across 5 continents, we sought to describe CVD risk factor distributions, examine associations between CVD risk and HIV characteristics, and characterize CV health among middle-aged PWH without known CVD.
DISCUSSION
Among 7382 participants in the global REPRIEVE trial, CV risk measured by the PCE risk score tracked with demographics and risk factors. HIV-related factors and immune function parameters were less strongly associated, but in a direction suggesting importance of immune dysfunction. The vast majority (90%) of this global population with low to moderate CVD risk demonstrated poor to intermediate health using a standardized assessment of CV health. Several components, including BMI, physical activity, and diet, did not relate to the PCE risk score, suggesting the critical need to assess and address these poor health characteristics to improve overall CVD outcomes in this population.
As expected, higher PCE score tracked well with its input components including age, sex, race, smoking, and systolic blood pressure [15]. Relationships with diabetes and especially hyperlipidemia were limited by trial entry requirements. Known risk factors not included in the PCE inputs also tracked with increasing scores, including family history of premature CVD, depression, and the metabolic abnormalities of obesity, metabolic syndrome, and waist circumference.
Several HIV parameters were modestly related to PCE risk score. However, the higher PCE risk among those with longer ART duration is potentially due to long-term adverse effects of HIV infection or various ART regimens on metabolic pathways [18], including lipids [19]. PCE risk also tended to be higher among those with entry NRTI-containing regimens that included ABC or TAF. A relationship between ABC and increased myocardial infarction rates has been found in some studies [20], possibly related to effects on platelet and endothelial function [21], but not in other studies [22]. In contrast, TAF was associated with higher PCE, possibly due to enrollment timing, as well as direct effects on lipids levels relative to TDF, or preferential use in higher risk groups [23]. Notably, neither integrase strand transfer inhibitor use nor BMI was associated with PCE risk. In this cross-sectional study, it is impossible to assess complex relationships between various ART regimens and CV risk, lipids and inflammation, or outcomes.
Lower nadir CD4 was associated with increased PCE risk score, suggesting that degree of initial immune dysfunction relates to traditional longer-term risk indices. These findings are consistent with current theories, supported by associations between coronary plaque and arterial inflammation in HIV [24, 25], that increased inflammation and immune activation may contribute to excess CVD risk in PWH [24-26]. The degree and directionality of these effects extends our knowledge of the potential biological impact of immunological dysfunction on risk in PWH and suggests that immunological effects may be reflected in the components of the PCE score, despite its lack of any HIV-specific elements. Future REPRIEVE analyses will compare more nuanced mechanistic measures of immune function [27] to PCE risk, providing further insights as to whether immunologic factors drive events through risk pathways not assessed in traditional scoring algorithms.
In contrast to scores predicting risk for future CV events, LS7 assesses CV health. It is inversely and closely related to CV outcomes in diverse populations even after adjustment for age, race, and sex and other characteristics, as shown in a meta-analysis of nine prospective cohort studies involving 12 878 participants [13]. The LS7 metrics include only potentially modifiable components, some of which overlap with PCE (health factors: blood pressure, total cholesterol, smoking), whereas others do not (lifestyle or health behaviors: diet, physical activity, BMI, glucose). To our knowledge, this is the first application of LS7 to a large PWH cohort. Overall, only 10% of individuals had ≥5 of 7 categories meeting criteria for ideal CV health, compared with nearly 17% in the 2011-12 National Health and Nutrition Examination Survey assessment, and over a third had poor CV health (≤2 of categories meeting ideal) [28]. Other cohorts show similar poor CV health, including Atherosclerosis Risk in Communities (ARIC), which showed that just 0.1% had all 7 categories meeting ideal criteria [29]. Of note, compared to the ARIC cohort, higher proportions of REPRIEVE participants had ideal status for BMI, diet, cholesterol, and glucose, but fewer met ideal criteria for smoking, physical activity, and blood pressure.
As expected, those characteristics common to LS7 and PCE showed progressive worsening with increasing risk category; however, the others did not. Thus, LS7 complements the PCE risk score for overall assessments of CV status and underscores its possible utility as a tool for guiding CV health improvement. Specifically, even among those with lowest PCE risk, there were many participants with poor diet, elevated BMI, and low physical activity. It is likely that CV health is poorer among the higher CVD risk PWH population not included in this trial. Our findings are congruent with previous data in a small cohort study showing PWH to be substantially more sedentary than demographically matched HIV-negative controls, although differences in healthy diet were not significant [30]. Ongoing research in this area is expected to shed more light on these modifiable components of CV health [31].
Although this study has considerable strengths, including use of a large sample size and global multiracial populations, it also has limitations in representing the overall population of PWH. Trial inclusion and exclusion criteria were related to risk scores, lipids, and other relevant factors which may have shaped some of the distributions. The study was not a randomized trial of ART, and thus our purpose was not to compare CVD risk/health between ART treatment groups but to examine whether such factors are associated with traditional risk/health algorithms. Ultimately, the ongoing REPRIEVE trial will examine CV risk and health estimates in relation to incident major adverse CV events.
CONCLUSION
Among 7382 REPRIEVE trial participants, the 10-year PCE-predicted CV risk score tracked well with demographics and other CV risk factors but was related less strongly to HIV characteristics or specific ART use. Ideal CV health was rare regardless of PCE risk score. Moreover, the PCE risk score did not capture common unhealthy behaviors, including poor diet, high BMI, and low physical activity. Our findings strongly suggest that key health behaviors should be assessed, in addition to standard risk, to better understand CV health in PWH. Furthermore, lifestyle interventions may be indicated regardless of CV risk estimate and/or conventional treatment. Ultimately, it will be important to assess how well the PCE and lifestyle-based behavior assessment algorithms can predict CVD risk over time in REPRIEVE and to determine the optimal risk/health stratification system in this population.
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