Most children used HAART with PI at some point during follow-up (1662 [78%] of 2122 children). The IR of hypercholesterolemia during HAART with PI use was 4.8 cases per 100 person-years (95% CI: 4.2 to 5.4). In contrast, the IR during use of HAART without PI was significantly lower, with 0.7 cases per 100 person-years (95% CI: 0.3 to 1.5), similar to the rate during periods of no ART use (0.5 cases per 100 person-years; 95% CI: 0.1 to 1.5). When children were using ART that was not a HAART regimen (which could include regimens with or without PIs), the IR was 1.4 cases per 100 person-years (95% CI: 0.9 to 2.2). Among children who were on a regimen of ART without HAART at some point during the study period, 11% of the person-time included PI use. The intermediate risk of hypercholesterolemia in this group is likely explained by the use of PIs by some children.
Boosted PI use, nonboosted PI use, and NNRTI use as well as younger age, lower viral load, and self-reported perfect adherence were significant risk factors for development of incident hypercholesterolemia (Table 3). The effects of boosted and nonboosted PIs were particularly strong and similar in magnitude. The adjusted HR for use of lopinavir-boosted PI was 14.0 (95% CI: 6.75 to 29.2), similar to that for boosted PI use that did not include lopinavir (13.5; 95% CI: 6.22 to 29.2). In addition, although we found that NNRTIs generally increased risk, there was no difference in the risk conferred by the specific use of efavirenz relative to that of other NNRTIs (primarily nevirapine) (for efavirenz use, HR = 1.41, 95% CI: 1.05 to 1.90; for other NNRTI use, HR = 1.25, 95% CI: 0.91 to 1.71). The use of NRTIs was not associated with the risk of developing hypercholesterolemia (including the specific use of stavudine). Children who, at a baseline interview of the person primarily responsible for medication dosing (the parent or guardian or the child), reported perfect adherence to ART use during the previous 3 days and those children with a nondetectable or low viral load were also more likely to develop hypercholesterolemia than were children with imperfect adherence or those with a higher viral load. Gender, race, an AIDS-defining condition at baseline, BMI, and CD4% at baseline showed no significant association for risk of hypercholesterolemia.
This is the first large prospective cohort study to examine the effect of PIs and other antiretroviral medications on the incidence of hypercholesterolemia among an HIV-infected pediatric population. In addition to the 13% of children with hypercholesterolemia at baseline, 13% developed hypercholesterolemia during the course of follow-up. Furthermore, the IR seemed to be constant over the period of follow-up, suggesting that the proportion of children with hypercholesterolemia is likely to continue to increase over time. We found that the use of regimens containing PIs greatly increased this incidence. Mechanisms hypothesized to explain the association between PIs and elevated lipid levels include their potential roles in increasing the synthesis of lipids by liver enzymes19 and inhibiting the proteins involved in lipid metabolism and adipocyte differentiation.20,21 NNRTI use, younger age, optimal viral suppression, and self-reported perfect adherence were also associated with increased incidence.
A concerning clinical implication of our findings is the potential for development of premature atherosclerotic disease in this group. Although longitudinal studies of the consequences of dyslipidemia in HIV-infected children have yet to be reported, it has been noted that HIV-infected children treated with HAART have elevations in their cholesterol similar to those seen in patients heterozygous for familial hypercholesterolemia and may have a similar risk for premature atherosclerotic disease.15 In the Bogalusa Heart Study, autopsies were performed on subjects aged 2 to 39 years. High BMI, elevated blood pressure, elevated serum concentrations of total and LDL cholesterol, and elevated triglycerides in childhood correlated with the extent of fibrous plaques found in the coronary arteries and aorta in children and young adults.22 The association of HIV and its management with other risk factors for cardiovascular disease is unclear. An earlier cross-sectional study in PACTG 219C found a positive association between hypercholesterolemia and elevated systolic blood pressure on univariate but not multivariate analysis and no association with BMI.11 Similar to this earlier study, we found younger age to be associated with increased incidence on multivariate analysis, adjusting for viral load and adherence. Although the explanation for this finding remains unclear, the youngest patients, who will have the longest duration of PI exposure, were the most likely to develop hypercholesterolemia.
Pediatricians are beginning to use lipid-lowering medications in HIV-infected children with dyslipidemia. In our study, 15 (5.4%) of the 277 children who developed hypercholesterolemia began lipid-lowering therapy. The American Academy of Pediatrics recommends a management strategy based on risk stratification by disease status, with consideration of cardiovascular risk factors and comorbidities.23 Although “chronic inflammatory disease” is listed as a criterion for placement in tier II or the “moderate risk” tier, HIV infection is not specifically addressed. Goals of therapy are recommended for BMI, blood pressure, fasting glucose, and LDL cholesterol. LDL cholesterol goals range from ≤160 mg/dL for the lowest risk tier to ≤100 mg/dL for the highest risk tier. Therapeutic lifestyle change is recommended as the initial intervention. For patients not achieving the goal of treatment with lifestyle change, disease-specific management, including drug therapy, is recommended. The class of agents known as statins reduces cholesterol biosynthesis through competitive inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis. These agents are preferred for the management of patients with isolated hypercholesterolemia.32 Although some statins have been approved for use in children and are recommended in a number of clinical circumstances by the American Academy of Pediatrics for children older than the age of 10 years, most statins are metabolized by the cytochrome P450 pathway and pharmacokinetic interactions with PIs may be significant.33 The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) is planning a safety and pharmacokinetic study of atorvastatin in children and youth being treated with a PI. This should provide useful information to facilitate the updating of dyslipidemia treatment guidelines for HIV-infected children.
Although our prospective study has significant strengths, including a large sample size facilitating a thorough assessment of risk factors and confounders, there are a number of limitations. Cholesterol measurements were generally obtained in the nonfasting state; thus, we are not able to report on LDL or HDL cholesterol or triglycerides. Nonfasting total cholesterol measurements are considered useful dyslipidemia screening tools for children and adolescents, however.34 Furthermore, there is good agreement between fasting and nonfasting total cholesterol measurements among adults when categories (high vs. normal) of cholesterol are compared.35 A study in HIV-infected children found no significant difference in group means for total cholesterol obtained in the fasting versus nonfasting state.12 Our study focuses on elevated total cholesterol as the sole metabolic complication. Adult and pediatric studies suggest that the overall prevalence of metabolic complications may be higher when one considers other disorders such as fat maldistribution, insulin resistance, bone disease, avascular necrosis, or mitochondrial toxicity.32,36
We did not collect information on factors such as diet, smoking, or family history of heart disease. Although these are important risk factors, most are unlikely to be associated with ART use; thus, they would not confound its association with hypercholesterolemia. Most children had a BMI z-score less than 2, and BMI was not associated with hypercholesterolemia risk.
Another potential limitation is that we did not consider the duration of ART exposure before the period of observation, and it is thus possible that our effect sizes were somewhat underestimated. Because inclusion of exposure duration would have likely increased the HRs for PI use, which were already large and statistically significant, the interpretation of our results is not affected.
The results of this study indicate that the use of PIs leads to a marked increase in total cholesterol levels among HIV-infected children and adolescents. Despite the potential negative consequences of treating HIV-infected children with PIs, the benefits associated with PI-based treatment outweigh the toxicities. Important questions remain, such as the incidence of other metabolic complications and their association with dyslipidemia, whether dyslipidemia in this group of children is associated with an increased risk of cardiovascular disease, and optimal management strategies for dyslipidemia in this group. Continued follow-up studies similar to PACTG 219C are needed to evaluate the long-term effects of ART on lipodystrophy, abnormal glucose metabolism, hypertension, abnormal bone mineralization, and lipid abnormalities.
The authors thank the children and families for their participation in PACTG/IMPAACT 219C and the individuals and institutions involved in the conduct of PACTG/IMPAACT 219C.
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The following institutions and individuals participated in PACTG protocol 219C, by order of enrollment: Baylor Texas Children's Hospital, Baylor, TX: Mary E. Paul, MD, Chivon D. Jackson, RN, BSN, ADN, Faith Minglana, RN, BSN, and Heidi Schwarzwald, MD; University of Florida, Jacksonville, FL: Mobeen H. Rathore, MD, Ayesha Mirza, MD, Kristy Champion, and Almer Mendoza; Chicago Children's Memorial Hospital, Chicago, IL: R. Yogev, and E. Chadwick; University of Puerto Rico, University Children's Hospital AIDS Program, San Juan, PR: Irma L. Febo, MD, Licette Lugo, MD, Ruth Santos, RN, and Ibet Heyer, RN; Bronx Lebanon Hospital Center, Bronx, NY; M. Purswani, S. Baksi, E. Stuard, and M. Dummit; San Juan Hospital, San Juan, PR: M. Acevedo, M. Gonzalez, L. Fabregas, and M.E. Texidor; University of Miami, Miami, FL: Gwendolyn B. Scott, MD, Charles D. Mitchell, MD, Claudia Florez, MD, and Joan Gamber; University of Medicine and Dentistry of New Jersey, Newark, NJ: Arlene Bardeguez, MD, Arry Dieudonne, MD, Linda Bettica, and Juliette Johnson; Charity Hospital of New Orleans and Earl K. Long Early Intervention Clinic, New Orleans, LA: M. Silio, T. Alchediak, C. Boe, M. Cowie, and R. Van Dyke; University of California, San Diego Mother, Child, and Adolescent HIV Program, San Diego, CA: Stephen A. Spector, MD, Rolando M. Viani, MD, MTP, Mary Caffery, RN, MSN, and Kimberly Norris, RN; Howard University Hospital, Department of Pediatrics, Washington, DC: Sohail Rana, MD, Helga Finke, MD, Patricia Yu, MS, and Jhoanna Roa, MD; Jacobi Medical Center, Bronx, NY: M. Donovan, R. Serrano, M. Burey, and R. Auguste; St. Christopher's Hospital for Children, Philadelphia, PA: J. Chen, and J. Foster; Baystate Medical Center Children's Hospital, Springfield, MA: B. W. Stechenberg, D. J. Fisher, A. M. Johnston, and M. Toye; Los Angeles County Medical Center/University of Southern California, Los Angeles, CA: J. Homans, M. Neely, L. S. Spencer, and A. Kovacs; Children's Hospital Boston, Boston, MA: S. Burchett, and N. Karthas; Children's Hospital of Michigan, Detroit, MI: E. Moore, and C. Cromer; St. Jude Children's Research Hospital, Memphis, TN: Aditya Gaur, MD, Katherine Knapp, MD, Nehali Patel, MD, and Marion Donohoe, RN, MSN, PNP; New York University School of Medicine/Bellevue Hospital, New York, NY: Maryam Minter, RN, Thomas Hastings, Seham Akleh, and William Borkowsky, MD; The Children's Hospital at Downstate, Brooklyn, NY: E. Handelsman, H. J. Moallem, D. M. Swindell, and J. M. Kaye; The Columbia-Presbyterian Medical Center and Cornell University-New York Presbyterian Hospital, New York, NY: A. Higgins, M. Foca, P. LaRussa, and A. Gershon; The Children's Hospital of Philadelphia, Philadelphia, PA: Steven D. Douglas, MD, Richard M. Rutstein, MD, Carol A. Vincent, CRNP, MSN, and Patricia C. Coburn, RN, BSN; Children's Hospital of Oakland, Oakland, CA: Ann Petru, MD, Teresa Courville, RN, MN, Katherine Eng, RN, PNP, and Karen Gold, RN, MA; University of California, San Francisco, Moffitt Hospital, San Francisco, CA: Diane W. Wara, MD, Nicole Tilton, PNP, and Mica Muscat, PNP; Children's Hospital, University of Colorado, Denver, Aurora, CO: E. McFarland, and C. Salbenblatt; Johns Hopkins University, Pediatrics, Baltimore, MD: N. Hutton, B. Griffith, M. Joyner, and C. Kiefner; Children's Hospital and Regional Medical Center, University of Washington, Seattle, WA: Michele Acker, MN, ARNP, Ann J. Melvin, MD, MPH, Kathleen M. Mohan, ARNP, and Suzanne Phelps, MS; Metropolitan Hospital Center, New York, NY: Mahrukh Bamji, MD, Indu Pathak, MD, Savita Manwani, MD, and Ekta Patel, MD; Children's National Medical Center, Washington, DC: Diana Dobbins, RN, MSN, Deidre Wimbley, RN, Tracy Perron, RN, and Hans Spiegel, MD, PhD; University of Massachusetts Medical School, Worcester, MA: K. Luzuriaga, and R. Moriarty; University of Alabama at Birmingham, Birmingham, AL: R. Pass, and M. Crain; University of Maryland School of Medicine, Baltimore, MD: D. Watson, J. Farley, K. Klipner, and C. Hilyard; Schneider Children's Hospital, New Hyde Park, NY: V. R. Bonagura, S. J. Schuval, C. Colter, and L. Campbell; Boston Medical Center, Boston, MA: Stephen I. Pelton, MD, E. R. Cooper, MD, Lauren Kay, RN, and Ann Marie Regan, PNP, MEd; University of Illinois, Chicago, IL: K. C. Rich, K. Hayani, M. Bicchinella, and J. Camacho; State University of New York, Stony Brook, NY: Sharon Nachman, MD, Denise Ferraro, RN, Jane Perillo, PNP, and Michele Kelly, PNP; North Broward Hospital District, Ft. Lauderdale, FL: Ana M. Puga, MD, Guillermo Talero, MD, James Blood, MSW, and Stefanie Juliano, MSW; Duke University, Pediatrics, Durham, NC: Carole Mathison, Kareema Whitfield, Felicia Wiley, RN, and Margaret Donnelly, PA; Harlem Hospital, New York, NY: S. Champion, M. Frere, M. DiGrado, and E. J. Abrams; Cook County Hospital, Chicago, IL: James B. McAuley, MD, Kenneth M. Boyer, MD, Maureen Haak, RN, MSN, and Jamie Martinez, MD; University of South Alabama, Birmingham, AL: Mary Mancao, MD, and Benjamin Estrada, MD; Connecticut Children's Medical Center, Hartford, CT: Juan C. Salazar, MD, MPH, and Gail Karas, RN; University of North Carolina at Chapel Hill, Chapel Hill, NC: Tom Belhorn, MD, PhD, Jean Eddleman, ACSW, CCSW, and Betsy Pitkin, RN; Ruiz Arnau University Hospital, Bayamon, PR: W. Figueroa, and E. Reyes; State University of New York Upstate Medical University, Syracuse, NY: L. B. Weiner, K. A. Contello, W. A. Holz, and M. J. Famiglietti; Children's Medical Center of Dallas, Dallas, TX: A. Winborn, G. Wendel; University of Florida at Gainesville, Gainesville, FL: R. Lawrence, J. Lew, C. Delany, and C. Duff; Children's Hospital at Albany Medical Center, Albany, NY: A. D. Fernandez, P. A. Hughes, N. Wade, and M. E. Adams; Lincoln Medical and Mental Health Center, Bronx, NY: D. Gomez, J. Sinanan; Phoenix Children's Hospital, Phoenix, AZ: J. P. Piatt, J. Foti, and L. Clarke-Steffen; Public Health Unit of Palm Beach County, West Palm Beach, FL: J. Sleasman, and C. Delaney; Medical College of Georgia, Augusta, GA: Stuart Foshee, MD, Chitra S. Mani, MD, Dennis L. Murray, MD, and Christopher White, MD; Yale University School of Medicine, New Haven, CT: Warren A. Andiman, MD, Leslie Hurst, MS, Janette de Jesus, MD, and Donna Schroeder, BS; Vanderbilt University Medical Center, Nashville, TN: G. Wilson; University of Rochester Medical Center, Rochester, NY: Geoffrey A. Weinberg, MD, Francis Gigliotti, MD, Barbra Murante, MS, RN, PNP, and Susan Laverty, RN; St. Joseph's Hospital and Medical Center, Paterson, NJ: N. Hutchcon, and A. Townley; Emory University Hospital, Atlanta, GA: S. Nesheim, and R. Dennis; University of South Florida, Tampa, FL: P. Emmanuel, J. Lujan-Zilberman, C. Graisberry, and S. Moore; Children's Hospital of the King's Daughters, Norfolk, VA: R. G. Fisher, K. M. Cunnion, T. T. Rubio, and D. Sandifer; Medical University of South Carolina, Columbia, SC: G. M. Johnson; University of Mississippi Medical Center, Jackson, MS: H. Gay, and S. Sadler; Harbor-UCLA Medical Center, Torrance, CA: Margaret A. Keller, MD, Nasser Redjal, MD, Spring Wettgen, RN, PNP, and Sheryl Sullivan, LVN; Mount Sinai Medical Center, New York, NY: D. Johnson; Children's Hospital of Los Angeles, Los Angeles, CA: J. Church, T. Dunaway, and C. Salata; Long Beach Memorial Hospital, Long Beach, CA: Susan Marks, RN, Karen Elkins, PNP, Jagmohan Batra, MD, and Audra Deveikis, MD; Robert Wood Johnson Medical School, New Brunswick, NJ: S. Gaur, P. Whitley-Williams, A. Malhotra, and L. Cerracchio; Sinai Children's Hospital, Chicago, IL: M. Dolan, J. D'Agostino, and R. Posada; The Medical Center, Pediatric, Columbus, GA: C. Mani, and S. Cobb; Medical College of Virginia, Richmond, VA: S. R. Lavoie, and T. Y. Smith; Cooper Hospital-University Medical Center, Camden, NJ: A. Feingold, and S. Burrows-Clark; University of Cincinnati, Cincinnati, OH: J. Mrus, and R. Beiting; Columbus Children's Hospital, Columbus, OH: M. Brady, J. Hunkler, and K. Koranyi; Sacred Heart Children's Medical Services of Florida, Pensacola, FL: W. Albritton; St. Luke's/Roosevelt Hospital Center, New York, NY: R. Warford, and S. Arpadi; Incarnation Children's Center, New York, NY: A. Gershon, and P. Miller; Montefiore Medical-Albert Einstein College of Medicine, Bronx, NY: A. Rubinstein, and G. Krienik; Children's Hospital of Los Angeles, Los Angeles, CA: A. Kovacs and E. Operskalski; San Francisco General Hospital, San Francisco, CA: D. Wara, A. Kamrin, S. Farrales, N. Tilton, and M. Muscat; Cornell University-New York Presbyterian Hospital, New York, NY: R. Johan-Liang, and K. O'Keefe; St. Louis Children's Hospital, St. Louis, MO: K. A. McGann, L. Pickering, and G. A. Storch; North Shore University Hospital, Manhasset, NY: S. Pahwa, and L. Rodriquez; and Oregon Health and Science University, Portland, OR: P. Lewis, and R. Croteau.