From the *Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine; and †Children's Healthcare of Atlanta, Atlanta, GA; ‡Pediatric Infectious Diseases, Rainbow Babies and Children's Hospital; and §Case Western Reserve University, Cleveland, OH.
G.A.M. has served as a consultant, speaker, and has received research funding from Bristol-Myers Squibb, GlaxoSmithKline, Gilead, Merck, Tibotec, and Abbott. G.A.M. currently chairs a DSMB for a Pfizer-funded study. A.C.R. has received research funding from Bristol-Myers Squibb, Cubist Pharmaceuticals, and GlaxoSmithKline.
It is now well established that HIV-infected individuals are at an increased risk of cardiovascular disease (CVD).1,2 In a health care system-based cohort study of adults, the unadjusted relative risk of acute myocardial infarction was 1.53 (95% confidence interval: 1.32 to 1.75; P < 0.0001) in HIV-infected individuals compared with non-HIV-infected individuals.2 Across all age groups, the rates of myocardial infarction were consistently higher for patients in the HIV cohort compared with the non-HIV cohort. Atherosclerosis formation begins early in childhood,3 and, therefore, accelerated CVD development likely occurs in HIV-infected children as well. Studies have demonstrated increased cross-sectional measures of carotid intima-media thickness, a marker of subclinical atherosclerosis and CVD risk, in HIV-infected children compared with healthy controls.4-6 With the advent of combination antiretroviral therapy (ART), HIV-infected children are expected to live well into adulthood. However, the increased CVD risk associated with HIV and/or ART presents new challenges and serious implications for quality of life and life expectancy for this population.
In this issue of J Acquir Immune Defic Syndr, 2 studies lend insight into the effects of HIV and ART on lipoprotein profiles, which may affect long-term CVD risk among HIV-infected children. First, Jacobson et al7 followed HIV-infected children in the Pediatric AIDS Clinical Trial Group (PACTG) 219C cohort to determine the clinical course and management of hypercholesterolemia, particularly investigating the effect of ART changes on total cholesterol (TC) levels. The authors had previously reported a high incidence and prevalence of hypercholesterolemia in this cohort of perinatally infected children.8,9 Here, they observe that approximately 2 of 3 children with incident or prevalent hypercholesterolemia did not resolve during the 2-year follow-up period, despite various ART changes in 27% of children, but only a small percentage of children initiating lipid-lowering medications. Second, Rhoads et al10 examined 447 HIV-infected children in an outpatient clinic to determine the effects of antiretrovirals on changes in lipoprotein profiles. In this study, the investigators found that there was no difference in lipoprotein profile changes among the children who started ART during the study period regardless of ART class or specific antiretroviral [protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI) versus efavirenz (EFV) versus nevirapine (NVP)]. However, they did observe significant yearly increases in all measured cholesterol subfractions [TC, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), non-HDL-C)] and trigylcerides (TG) among all ART-treated children regardless of antiretroviral type compared with children not on ART. Increases in non-HDL-C were most significant with PI-containing regimens.
One important finding in Jacobson et al was that although 27% of children with hypercholesterolemia made at least 1 ART regimen change during the 2-year study period, most of the changes were not those that are known in the adult population to be associated with beneficial lipoprotein profile changes.11-14 There is no reason to think that children's lipoprotein profile changes with ART classes and specific antiretrovirals would be any different from that which is observed in adults. And, in fact, multiple studies, including the current ones, demonstrate that lipoprotein profiles in HIV-infected children before and after ART initiation follow patterns seen in the adult HIV population.15-19 Knowing this, pediatric HIV providers should consider adult guidelines to inform their decisions in HIV-infected children, until specific pediatric guidelines are developed. Interestingly, however, their analysis indicated that uncontrolled viremia and NOT hypercholesterolemia predicted change in ART regimens. Therefore, ART changes were likely made irrespective of lipoprotein profiles and were guided by other issues, such as virological failure or medication side effects. This raises the issue that HIV-infected children have additional challenges that must be considered before changing ART regimens to improve lipoprotein profiles. Foremost, HIV-infected children have fewer antiretroviral options than adults due to their inability to swallow pills, lower body weights, ongoing growth and development, and/or lack of efficacy or safety data in the pediatric population.
Although changing antiretrovirals may be an option to improve lipoprotein profiles in HIV-infected children, especially those on a PI-containing regimen, changing regimens always comes with a risk of virological failure. Because this would limit a child's ART choices further, the risks and benefits must be weighed carefully. A number of adult studies have evaluated the lipid effects associated with changing antiretroviral regimens. In a randomized trial, subjects switching from lopinavir/ritonavir to ritonavir-boosted atazanavir (ATV)/r had significant decreases in TC and TG after 48 weeks.20 Similarly, a randomized open-label trial showed that ART initiation with ATV/r had a modest but larger increase in all lipid parameters and TG when compared with ATV.21 However, although the study was not powered to test noninferiority, there was a trend toward more virologic failure in ATV arm at week 96. This raises a crucial point as follows: in such a vulnerable pediatric patient population, maintaining an individual child on a regimen that is known to provide virological suppression may be more important than the modest lipid changes which would accompany a regimen change. One exception may be a switch from stavudine (d4T) to tenofovir, as some children are still on d4T due to their limited ART choices. In adults, the lipid changes observed with this switch were significant and sustained,22 and such a change would also reduce the risk of developing lipodystrophy which may accompany the use of d4T. Switch studies in children have been sparse and small, but results have mirrored adult studies.23,24
Because maintaining virologic suppression is paramount in HIV care, lipid-lowering agents may offer a better and safer alternative to switching ART regimen. A 12-month, open-label study of 130 adult subjects compared initiating a lipid-lowering agent (either bezafibrate or pravastatin) versus switching ART therapy from a PI-based to an NNRTI-based regimen.25 Pravastatin or bezafibrate were significantly more effective in the management of hyperlipidemia than switching ART to an NNRTI. Other studies have shown a reduction in TC and LDL-C of 20%-35% with the use of statins, which inhibit HMG-CoA reductase and the liver's ability to produce LDL-C.26 One striking observation in the Jacobson study was the low percentage of children with hypercholesterolemia who initiated lipid-lowering medications, particularly statins, and the time with which it took to initiate a medication after development of hypercholesterolemia. Likewise, Rhoads et al observed 20 children who may have met American Academy of Pediatrics criteria for pharmacologic intervention during the study period depending on associated risk factors; yet, no child received any lipid-lowering medications. As the first authors point out, this may be due to the lack of cholesterol guidelines specific for HIV-infected children. Although the American Academy of Pediatrics advises statin use for healthy children with LDL-C levels >190 mg/dL only after dietary interventions have failed (or >160 mg/dL with a family history of premature atherosclerosis or ≥2 additional risk factors present or >130 mg/dL if diabetes mellitus is present), these guidelines likely are not relevant to HIV-infected children. Pediatric patients with chronic inflammatory conditions are considered “high-risk”, and HIV-infected children should be included in this category. Importantly, when using the LDL-C cut-off for children with inflammatory conditions (>130 mg/dL),27 10.5% of the children in Rhoads et al met criteria for pharmacologic intervention and 60% remained in this range at 1 year. Notably, data with statins are sparse even in HIV-infected adults, and it is unclear if statins may modulate inflammation and affect CVD risk independently of lipids, such as has been shown in the general population.28 Indeed, a recent study showed that statins decrease immune activation in HIV-infected adults.29
Significant data have emerged in the last few years, which implicate excess inflammation and abnormal coagulation as the cause of many of the long-term complications emerging with chronic HIV infection, including CVD, especially when viremia is not controlled with ART.30-38 HIV-infected children are no exception to this: significant relationships between carotid intima-media thickness and inflammation markers have also been observed in this population and an increased high-sensitivity C-reactive protein level in HIV-infected children compared with healthy controls.5,39 Thus, it should be emphasized that although both of these studies focused on the increased CVD risk associated with lipoprotein profile abnormalities, the use of ART as a means of decreasing inflammation, improving endothelial dysfunction, and ultimately minimizing CVD risk likely attenuates this risk.
Adult HIV studies have shown inflammatory markers and surrogate markers of CVD improve with ART,34,35,40 and continuous therapy decreases cardiac-related deaths.31 This seems to be true for HIV-infected children and young adults as well.41,42
Thus, lipid abnormalities represent only a part of the increased CVD risk associated with HIV infection. Moreover, using ART to suppress viral replication and inflammation seems to be an important strategy for decreasing CVD risk among HIV-infected children and may overshadow the lipid abnormalities associated with the use of certain antiretrovirals. Regardless, however, these current J Acquir Immune Defic Syndr studies emphasize the urgent need to develop guidelines specifically for HIV-infected children, where there is an opportunity to minimize CVD risk early, well before the onset of established disease. Likely, a combined approach will achieve the best results as follows: selecting a lipid-friendly ART regimen while achieving virological suppression, along with aggressive lifestyle and pharmacologic interventions. Statin use may be used in the future, not only to improve lipids, but also as a means of further decreasing inflammation. Similarly, biomarker monitoring or initiation of anti-inflammatory medications may also prove to be beneficial. Formal guidelines are the first crucial step in minimizing CVD complications and maximizing quality of life in this vulnerable population.
1. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-uninfected individuals: a population-based cohort study. Clin Infect Dis
2. Triant VA, Lee H, Hadigan C, et al. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab
3. Berenson GS, Srinivasan SR, Bao W, et al. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med
4. Giuliano Ide C, de Freitas SF, de Souza M, et al. Subclinic atherosclerosis and cardiovascular risk factors in HIV-infected children: PERI study. Coron Artery Dis
5. McComsey GA, O'Riordan M, Hazen SL, et al. Increased carotid intima media thickness and cardiac biomarkers in HIV infected children. AIDS
6. Charakida M, Donald AE, Green H, et al. Early structural and functional changes of the vasculature in HIV-infected children: impact of disease and antiretroviral therapy. Circulation
7. Jacobson DL, Williams P, Tassiopoulos K, et al. Clinical management and follow-up of hypercholesterolemia a perinatally HIV-infected children enrolled in the PACTG 219C study. J Acquir Immune Defic Syndr
8. Farley J, Gona P, Crain M, et al. Prevalence of elevated cholesterol and associated risk factors among perinatally HIV-infected children (4-19 years old) in Pediatric AIDS Clinical Trials Group 219C. J Acquir Immune Defic Syndr
9. Tassiopoulos K, Williams PL, Seage GR III, et al. Association of hypercholesterolemia incidence with antiretroviral treatment, including protease inhibitors, among perinatally HIV-infected children. J Acquir Immune Defic Syndr
10. Rhoads MP, Lanigan J, Smith CJ, Lyall H. Effect of specific antiretroviral therapy (ART) drugs on lipid changes and the need for lipid management in children with HIV. J Acquir Immune Defic Syndr
11. Colafigli M, Di Giambenedetto S, Bracciale L, et al. Cardiovascular risk score change in HIV-1-infected patients switched to an atazanavir-based combination antiretroviral regimen. HIV Med
12. Flammer AJ, Vo NT, Ledergerber B, et al. Effect of atazanavir versus other protease inhibitor-containing antiretroviral therapy on endothelial function in HIV-infected persons: randomised controlled trial. Heart
13. Sension M, Andrade Neto JL, Grinsztejn B, et al. Improvement in lipid profiles in antiretroviral-experienced HIV-positive patients with hyperlipidemia after a switch to unboosted atazanavir. J Acquir Immune Defic Syndr
14. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, randomised controlled trials. Lancet
15. Lainka E, Oezbek S, Falck M, et al. Marked dyslipidemia in human immunodeficiency virus-infected children on protease inhibitor-containing antiretroviral therapy. Pediatrics
16. Shafran SD, Mashinter LD, Roberts SE. The effect of low-dose ritonavir monotherapy on fasting serum lipid concentrations. HIV Med
17. Melvin AJ, Lennon S, Mohan KM, et al. Metabolic abnormalities in HIV type 1-infected children treated and not treated with protease inhibitors. AIDS Res Hum Retroviruses
18. Riddler SA, Li X, Chu H, et al. Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy. HIV Med
19. Carter RJ, Wiener J, Abrams EJ, et al. Dyslipidemia among perinatally HIV-infected children enrolled in the PACTS-HOPE cohort, 1999-2004: a longitudinal analysis. J Acquir Immune Defic Syndr
20. Mallolas J, Podzamczer D, Milinkovic A, et al. Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study. J Acquir Immune Defic Syndr
21. Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without ritonavir, as part of once-daily highly active antiretroviral therapy regimens in antiretroviral-naive patients. J Acquir Immune Defic Syndr
22. Llibre JM, Domingo P, Palacios R, et al. Sustained improvement of dyslipidaemia in HAART-treated patients replacing stavudine with tenofovir. AIDS
23. Gonzalez-Tome MI, Amador JT, Pena MJ, et al. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children. BMC Infect Dis
24. McComsey G, Bhumbra N, Ma JF, et al. Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study. Pediatrics
25. Calza L, Manfredi R, Colangeli V, et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS
26. Calza L, Manfredi R, Chiodo F. Statins and fibrates for the treatment of hyperlipidaemia in HIV-infected patients receiving HAART. AIDS
27. Kavey RE, Allada V, Daniels SR, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation
28. Mora S, Ridker PM. Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER)—can C-reactive protein be used to target statin therapy in primary prevention? Am J Cardiol
29. Ganesan A, Crum-Cianflone N, Higgins J, et al. High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. J Infect Dis
30. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med
31. Phillips AN, Carr A, Neuhaus J, et al. Interruption of antiretroviral therapy and risk of cardiovascular disease in persons with HIV-1 infection: exploratory analyses from the SMART trial. Antivir Ther
32. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med
33. Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet
34. Ross AC, Armentrout R, O'Riordan MA, et al. Endothelial activation markers are linked to HIV status and are independent of antiretroviral therapy and lipoatrophy. J Acquir Immune Defic Syndr
35. Torriani FJ, Komarow L, Parker RA, et al. Endothelial function in human immunodeficiency virus-infected antiretroviral-naive subjects before and after starting potent antiretroviral therapy: The ACTG (AIDS Clinical Trials Group) Study 5152s. J Am Coll Cardiol
36. McComsey G, Smith K, Patel P, et al. Similar reductions in markers of inflammation and endothelial activation after initiation of abacavir/lamivudine or tenofovir/emtricitabine: the HEAT study [abstract 732]. Presented at: 17th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2009; San Francisco, CA.
37. Kristoffersen US, Kofoed K, Kronborg G, et al. Reduction in circulating markers of endothelial dysfunction in HIV-infected patients during antiretroviral therapy. HIV Med
38. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV infection with acute myocardial infarction. J Acquir Immune Defic Syndr
39. Ross AC, Storer N, O'Riordan MA, et al. Longitudinal changes in carotid intima-media thickness and cardiovascular risk factors in human immunodeficiency virus-infected children and young adults compared with healthy controls. Pediatr Infect Dis J
40. Kingsley LA, Cuervo-Rojas J, Munoz A, et al. Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study (see comment). AIDS
41. Ross AC, O'Riordan MA, Storer N, et al. Heightened inflammation is linked to carotid intima-media thickness and endothelial activation in HIV-infected children. Atherosclerosis
42. Ross A, Storer N, O'Riordan M, et al. Longitudinal changes in carotid intima-media thickness (cIMT) in HIV-infected children (abstract 153). Presented at: 18th Conference on Retroviruses and Opportunistic Infections; February 27-March 2, 2011; Boston, MA.