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Aggregate Risk of Cardiovascular Disease among Adolescents Perinatally Infected with the Human Immunodeficiency Virus
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"Our observation is also consistent with studies among HIV-infected adults that show the risk for vascular disease with ongoing inflammation is still increased in the presence of viral suppression."
"In conclusion, a substantial proportion of perinatally HIV-infected adolescents have PDAY scores reflecting increased aggregate atherosclerotic risk factor burden. PDAY [Pathobiological Determinants of Atherosclerosis in Youth] scores may be useful in identifying and tracking such high risk adolescents. Our findings suggest lifestyle modifications (e.g., diet and exercise) and switching to new antiretroviral regimens less likely to cause metabolic abnormalities should be considered.41 Finally, our study contributes to growing literature showing increased global risk for premature CVD disease morbidity and mortality in the perinatally HIV-infected population, including risk of cardiomyopathy and cardiometabolic disease.7-15,42,43 A comprehensive assessment and treatment plan based on validated screening and interventions may be useful for those at highest risk in the perinatally HIV-infected population......Forty-eight percent of perinatally HIV-infected youth had high scores; with 12% having scores associated with combinations of dyslipidemia plus high individual score risk factors such as obesity, high blood pressure, and hyperglycemia."
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Aggregate Risk of Cardiovascular Disease among Adolescents Perinatally Infected with the Human Immunodeficiency Virus
Circulation. published online December 23, 2013
Kunjal Patel, DSc, MPH1,2; Jiajia Wang, MS2; Denise L. Jacobson, PhD, MPH2; Steven E. Lipshultz, MD, FAAP, FAHA3; David C. Landy, PhD, MPH4; Mitchell E. Geffner, MD5; Linda A. DiMeglio, MD, MPH6; George R. Seage III, DSc, MPH1,2; Paige L. Williams, PhD2; Russell B. Van Dyke, MD7; George K. Siberry, MD, MPH8; William T. Shearer, MD, PhD9; Luciana Young, MD, FACC10; Gwendolyn B. Scott, MD, MS4; James D. Wilkinson, MD, MPH4; Stacy D. Fisher, MD11; Thomas J. Starc, MD12; Tracie L. Miller, MD, SM4 for the Pediatric HIV/AIDS Cohort Study (PHACS)
1Dept of Epidemiology, Harvard School of Public Health, Boston, MA; 2Center for Biostatistics in AIDS Research (CBAR), Boston, MA; 3Dept of Pediatrics, Wayne State University School of Medicine, Children's Hospital of Michigan, Detroit, MI; 4Division of Pediatric Clinical Research and Division of Pediatric Infectious Disease and Immunology, Dept of Pediatrics, University of Miami Miller School of Medicine, Miami, FL; 5Saban Research Institute of Children's Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA; 6Section of Pediatric Endocrinology and Diabetology, Dept of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; 7Dept of Pediatrics, Tulane University Health Sciences Center, New Orleans, LA; 8Maternal and Pediatric Infectious Disease Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD; 9Dept of Pediatrics, Baylor College of Medicine, Texas Children's Hospital, Houston, TX; 10Dept of Pediatrics, Northwestern University Feinberg School of Medicine, Children's Memorial Hospital,
Chicago, IL; 11Division of Cardiology, University of Maryland School of Medicine, Baltimore, MD; 12Dept of Pediatrics, Division of Pediatric Cardiology, Presbyterian Hospital/Columbia University, College of Physicians and Surgeons, New York City, NY
Abstract
Background-Perinatally HIV-infected adolescents may be susceptible to aggregate atherosclerotic cardiovascular disease (CVD) risk, as measured by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) coronary arteries (CA) and abdominal aorta (AA) risk scores, due to prolonged exposure to HIV and antiretroviral therapy.
Methods and Results-CA and AA PDAY scores were calculated for 165 perinatally HIV-infected adolescents, using a weighted combination of modifiable risk factors: dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. Demographic and HIV-specific predictors of scores ≥1 were identified and trends in scores over time were assessed. 48% and 24% of the perinatally HIV-infected adolescents had CA and AA scores ≥1, representing increased CVD risk factor burden. Significant predictors of CA scores ≥1 included male sex, history of an AIDS-defining condition, longer duration of use of a ritonavir-boosted protease inhibitor, and no prior use of tenofovir. Significant predictors of AA scores ≥1 included suppressed viral load, history of an AIDS-defining condition, and longer duration of boosted protease inhibitor use. No significant changes in CA and AA risk scores were observed over the 4-year study period.
Conclusions-A substantial proportion of perinatally HIV-infected youth have high PDAY scores reflecting increased aggregate atherosclerotic CVD risk factor burden. High scores were predicted by HIV disease severity and boosted protease inhibitor use. PDAY scores may be useful in identifying high-risk youth who may benefit from early lifestyle or clinical interventions.
Results
The 165 perinatally HIV-infected adolescents in the study population were 15-19 years old (median age: 16.7 years) at their most recent visit with a PDAY score (Table 1). Forty-nine percent were male. Sixty-eight percent self-identified as black and 24% as Hispanic. At their most recent visit with a PDAY score, the majority (57%) of the adolescents had CD4 counts >500 cells/mm3, but a large proportion (41%) had a history of immunosuppression as evidenced by a low nadir CD4 count (<200 cells/mm3). A similar pattern of disease severity over time was observed with HIV viral load where 59% of the study population was virologically suppressed
(<400 copies/mL) at their most recent visit, but 68% had a history of viral load >100,000 copies/mL. Almost all of the adolescents had prior HAART exposure (97%). Seventy-four percent had been exposed to a boosted protease inhibitor regimen, with 58% currently on a boosted protease inhibitor as of their most recent visit.
Figure 1 shows the distribution of most recent CA and AA scores in the study population. Forty-eight percent had CA scores >/=1 with 24%, 16%, and 12% having CA scores >/=2, >/=3, and >/=4, respectively. High CA scores were primarily attributed to increased levels of non-HDL cholesterol, with additional risk from low levels of HDL cholesterol and high BMI (Table 2, Supplemental Table 2). Few adolescents were defined as hypertensive (1%) or hyperglycemic (1%), and none were defined as heavy smokers. Two adolescents with CA scores >/=10 had elevated levels of non-HDL cholesterol in the range of 160-189 mg/dL and were obese (BMI >30 kg/m2). Twenty-four percent of the study population had AA scores >/=1. Ten percent, 3%, and 1% had AA scores >/=2, >/=3, and >/=4, respectively. High AA scores were also primarily attributable to dyslipidemia.
Univariable predictors of CA scores >/=1 versus /=1 at p<0.05 with a final model c-statistic of 0.74 (Table 4). Results were consistent among the virologically-suppressed subset of the population (Supplemental Table 4).
Univariable predictors of AA scores >/=1 versus 0 at the p<0.10 level included current HIV viral load <400 copies/mL, CDC category C disease, current HAART use, current and prior use of a boosted protease inhibitor, a longer cumulative duration of boosted protease inhibitor use, current and prior use of lopinavir/ritonavir, a longer cumulative duration of lopinavir/ritonavir use, current abacavir use, current lamivudine use, and no prior tenofovir use (Table 3). In the final model, current HIV virologic suppression (<400 copies/mL versus 401-5,000 copies/mL), CDC clinical category C disease (relative to category B), and longer cumulative duration of boosted protease inhibitor use significantly predicted AA scores >/=1 at p<0.05 with a total model c-statistic of 0.84 (Table 5). Results of sensitivity analyses were consistent with those observed in the overall population (Supplemental Table 5).
Figure 2 shows the mean PDAY scores during the 4 year study follow-up period (mean follow-up of study population: 2.5 years). The slope of the CA scores was 0.10 per year and did not significantly change over time (95% CI: -0.05, 0.24, p=0.19). AA scores were also stable over time, with a slope of 0.03 per year (95% CI: -0.03, 0.08, p=0.34).
Discussion
Previous studies of perinatally HIV-infected children raised concern regarding increased CVD risk due to distributions of individual risk factors in this population.7-15 Our study uniquely sought to measure and describe aggregate CVD risk due to the combination of risk factors in perinatally HIV-infected youth by utilizing the validated PDAY scoring system which integrates individual risk factors into a single score for the CA and AA. Forty-eight percent of perinatally HIV-infected youth had high scores; with 12% having scores associated with combinations of dyslipidemia plus high individual score risk factors such as obesity, high blood pressure, and hyperglycemia.
Twenty-two percent of our study population had non-HDL cholesterol levels >/=130 mg/dL and 29% had HDL cholesterol <40 mg/dL. These findings are consistent with the high prevalence of dyslipidemia observed in perinatally HIV-infected cohorts compared to national youth estimates.7-10,13, 30 The prevalence of obesity in our study population was 13% which is lower than the 18% prevalence of obesity recently reported among adolescents in the United States.31 This is consistent with previous studies.9,10 However, a recent study showed that HIV-infected children have similar trends in obesity relative to the general population.32 The combination of dyslipidemia and obesity in the perinatally HIV-infected population would further the concern for premature atherosclerotic CVD.
Males in our study population were more likely to have high CA scores compared to females. Among studies of CVD risk factors that evaluated sex differences among perinatally HIV-infected adolescents, one found significantly higher cholesterol levels in males relative to females.7 Three found no sex differences in lipodystrophy or insulin resistance,12-14 while three others found females to have a body fat distribution associated with increased CVD risk.10,11 Independent lesion 18
A history of an AIDS-defining event also predicted higher PDAY scores in our study. Low levels of HDL cholesterol, often associated with inflammation and endothelial activation, are reported in HIV-infected adults with AIDS or untreated HIV infection.33,34 Also, independent of traditional CVD risk factors, HIV disease severity is correlated with higher levels of T-cell activation that is further associated with the presence of subclinical carotid artery lesions.35 In our study, suppressed HIV viral loads also predicted high PDAY scores for the AA relative to HIV viral loads in the 401-5000 copies/mL range. These effects may reflect toxicities associated with exposure to antiretroviral medications, as children currently on effective therapy are likely to have suppressed viral loads. Our observation is also consistent with studies among HIV-infected adults that show the risk for vascular disease with ongoing inflammation is still increased in the presence of viral suppression.35
As expected from prior studies in HIV-infected youth,7-15 boosted protease inhibitor use was a strong predictor of high CA and AA scores in our study population. Protease inhibitors promote hyperlipidemia by upregulating fatty acid and cholesterol biosynthesis and secretion, and by increasing lipoprotein production in the liver.36 Protease inhibitors can also suppress leptin expression and glucose transporter type 4 activity in adipocytes, thereby promoting lipodystrophy, insulin resistance and diabetes.36 While 5-8 years of exposure to boosted protease inhibitors predicted high CA and AA scores, greater than 8 years of exposure did not. This may be due to a lack of power to observe a significant effect due to few observed events among those with greater than 8 years of exposure. Alternatively our results may reflect clinician practice to switch children with preliminary indications of hyperlipidemia off of boosted protease inhibitors to more lipid friendly regimens.
A recent study of HIV-infected adults found tenofovir was significantly associated with progression of subclinical atherosclerosis, mediated perhaps through the lack of reduction in plasma monocyte chemotactic protein 1 levels relative to therapy with abacavir and lamivudine.37 Among our population of perinatally HIV-infected adolescents, however, tenofovir use predicted a lower likelihood of having high CA scores, consistent with other studies among HIV-infected adults showing improvement of dyslipidemia and arterial stiffness with nucleoside reverse transcriptase inhibitor switches to tenofovir.38 With these contrasting results, the association between tenofovir and CVD requires further investigation.
Over our 4-year study follow-up, there were no significant changes in CA or AA scores. We may be observing the consistent tracking of CVD risk factors over time or the duration of follow-up of our cohort may not have been sufficiently long to observe the acquisition of more adult lifestyle risk factors, such as smoking and physical inactivity. Continued follow-up of adolescents in our study as they age into adulthood will be necessary to better evaluate longitudinal trends in CVD risk and identify associated factors.
Our study had some limitations. We were unable to validate the PDAY scoring system against non-invasive measures of atherosclerosis or CVD events. The Adolescent Master Protocol did not utilize these measures and there is a low probability of observing CVD events in our relatively young study population. The CA and AA risk scores utilized in this study were developed from autopsy data, so the definitions of some of the risk factors (e.g., hypertension) were adapted using measures available in clinical practice. The difference in definitions may, therefore, not directly correlate with the odds ratio interpretations of the PDAY risk scores as stated by McMahan et al.18 We utilized the PDAY score as an estimate of the aggregate atherosclerotic CVD risk in our population. The PDAY score, however, may underestimate the risk of atherosclerotic lesions in this population because of the independent effects of HIV and antiretroviral therapy on the development and progression of atherosclerosis.35
Studies among HIV-infected adults suggest that risk scores incorporating both traditional and HIV-specific parameters may better predict CVD risk in HIV-infected populations.39,40 Although our study has a relatively small sample size compared to other studies that have utilized PDAY scores,22-24 it represents an understudied population of perinatally HIV-infected youth aging into young adulthood.
In conclusion, a substantial proportion of perinatally HIV-infected adolescents have PDAY scores reflecting increased aggregate atherosclerotic risk factor burden. PDAY scores may be useful in identifying and tracking such high risk adolescents. Our findings suggest lifestyle modifications (e.g., diet and exercise) and switching to new antiretroviral regimens less likely to cause metabolic abnormalities should be considered.41 Finally, our study contributes to growing literature showing increased global risk for premature CVD disease morbidity and mortality in the perinatally HIV-infected population, including risk of cardiomyopathy and cardiometabolic disease.7-15,42,43 A comprehensive assessment and treatment plan based on validated screening and interventions may be useful for those at highest risk in the perinatally HIV-infected population.
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