One hundred three children started treatment during the study period. Median CD4 nadir at the start of treatment was 250 (IQR: 150, 450) cells per milliliter. Seventy-nine (77%) started on NNRTI-based combinations of which 34 included NVP and 45 EFV. Fewer children were started on a PI regimen 19 (19%), of which 10 (10%) were on LPV/RTV and 9 (9%) were on NFV.
Before starting ART, TC levels in naive children (n = 95) were within the normal range (median: 3.4, IQR: 2.8-3.9).28 In children for whom data were available (n = 50), HDL-C was below the normal range (median: 0.8, IQR: 0.5-0.9). There were no associations between VL or CD4 count and TC, LDL, HDL, or TG in children unexposed to ART.
ARV-Naive Children Starting ART
One hundred three children started ART for the first time during the study period. Eighty-two had a TC measurement recorded before starting treatment and 1 year later (Figure). There was no significant difference in cholesterol changes from baseline between those children starting on EFV-containing, NVP-containing, PI-containing, and NNRTI-only regimens with respect to TC (P = 0.50), TG (P = 0.25), LDL (P = 0.24), HDL (P = 0.13), and non-HDL levels (P = 0.16).
Table 2 displays the mixed-effects modelling of individual ART effects on TC, TG, HDL, LDL, and non-HDL levels in all children as increase in mmol/L per year of exposure (0-1, 1-2, 2-3, 3-4, and >4 years) compared with no exposure. Data are presented as yearly exposure increases due to the effects not being linear. Sensitivity analyses indicated that the results presented in Table 2 were robust to changes. Unadjusted estimates of the effects of the drugs were similar to the adjusted results presented with the following small exceptions. The impact of NVP on non-HDL and LDL increased moderately in the multivariate analysis, and the effect of EFV on HDL was attenuated (data not shown). However, all results maintained the same significance and trend. Overall, all 4 drugs were significantly associated with increases in all 5 cholesterol subgroups. Abacavir was included in these analyses but was not found to be associated with cholesterol changes (data not shown).
After adjustment for potential confounders, those with 0- to 1-year cumulative exposure to NVP had a median 0.27 higher TC compared to those with no exposure. This increased to 0.57 at 2-3 years before levelling off with time (global P < 0.0001). Initial EFV exposure was associated with 0.28 higher TC compared with no exposure, which remained elevated; those with 1- to 2-year and 2- to 3-year cumulative EFV exposure had TC levels 0.28 and 0.29 higher than those with no exposure (global P < 0.0001). Those with 0- to 1-year and 1- to 2-year NFV exposure had 0.48 and 0.68 higher TC compared with no NFV exposure (P < 0.0001). Cumulative exposure of 0-1 year to LPV/RTV was associated with 0.46 higher TC compared to those with no exposure and continued to increase with prolonged exposure (P < 0.0001). Exposure to NVP was associated with lower TG levels, whereas exposure to EFV, NFV, and LPV was associated with higher TG.
NNRTIs were associated with significant increases in HDL (Table 2). Initial exposure to NVP and EFV was associated with an increased HDL (0.20 and 0.12 mmol/L, respectively at 0-1 year). These continued to increase to 0.34 and 0.19, respectively, at 1-2 years, and both remained constant thereafter (P < 0.0001). In contrast, the effect of PI on HDL although statistically significant is of little clinical importance.
LDL increased significantly with all 4 medications. The largest increases occurred with NFV, 0.39 at 0- to 1-year up to 0.96 at >4-year exposure (P < 0.0001). The lowest impact on LDL was made by EFV that gradually rose from 0.12 at 0-1 year, reaching a maximum of 0.45 at >4 years (P = 0.02).
The greatest difference between PIs and NNRTIs is demonstrated by non-HDL. Here, LPV/RTV increases non-HDL by 0.43 millimoles per year in the first 0- to 1-year and by 0.8 millimoles per year at >4-year exposure (P = 0.007). NFV has a larger earlier impact, increasing non-HDL by 0.92 mmol/L by 2- to 3-year exposure. This settles to 0.57 increase per year at >4-year exposure (P < 0.0001). The NNRTIs have a more modest impact on non-HDL as more of their TC count is HDL. NVP increases by 0.2-0.39 millimoles per year (P < 0.0001), and EFV increases between 0.14 and 0.29 per year of exposure (P = 0.01).
Children Meeting Criteria for Possible Pharmacological Intervention
Using AAP guidelines for pharmacological intervention,26 we identified 17 children during the study period with persistently raised levels above the “borderline” (LDL > 4.1 mmol/L) threshold for children with 2 or more risk factors and 3 children with persistently raised levels above the “intervention” (LDL > 4.9 mmol/L) threshold (Table 3). Of these 3, all were older than 8 years and would potentially be eligible for medical treatment of hypercholesterolemia under these guidelines. For the 17 children above the borderline cutoff, the median (IQR) time between the first and second high values was 98 (72-110) days. Ten (59%) (2.2% of the total population) of the borderline group were older than 8 years. Both groups had BMI z scores above average, and most were ART experienced. In the group eligible for intervention, all were ART experienced with a median of 8.1 (2.7-11.9) years of exposure. At 6 months and 1 year after meeting the criteria, the median LDL level was 4.8 (4.2-5.4) and 4.2 (3.5-5.8), respectively. One child remained eligible for treatment at 1 year. None had an ARV treatment switch. The borderline group at 6 months and 1 year had LDL levels of 4.1 (3.1-4.7) and 4.3 (3.5-4.5), respectively. At 1 year, there were 4 missing values and 8 of 13 remained above the cutoff.
Forty-seven (10.5%) children were above the 95th percentile for LDL 3.33 mmol/L (130 mg/dL), a suggested intervention cutoff for children with inflammatory conditions,27 and 25 of the 47 children (53.2%) were older than 8 years. At 1 year, despite conservative management, LDL level remained >3.33 mmol/L in 18 (58.1%) cases. The time between the first and second high values was 91 (63-119) days. All children had dietary and exercise advice, but none received lipid-lowering medication during the study.
It is difficult to separate the impact of HIV infection from ART on serum lipid concentrations. Research from the pre-ART era showed LDL and TG to increase as HIV progressed to AIDS.29 Our study of children starting ART before the onset of AIDS found no association between TC, LDL, TG or non-HDL, and VL or CD4 count. However, pre-ART protective HDL is low, with a median (IQR) of 0.8 (0.5-0.9) mmol/L.
For children on ART, TC levels were higher among those exposed to either NVP or LPV/RTV. Concentrations rose faster and remained elevated longer than for the NNRTIs. Cross-sectional studies have reported elevations in TC between 1 and 1.6 mmol/L in children on PIs compared with those not on PIs,7-9,11 which are greater than those reported here. However, we looked at rates of change rather than maximum increases; therefore, these results are not directly comparable. The increase in TC associated with NFV seems to be driven by non-HDL (primarily made up of LDL), whereas increased LPV/RTV exposure was associated with increases in HDL and non-HDL (both TG and LDL effected). Additionally, whereas lipid levels continued to increase after up to 4-year cumulative LPV/RTV exposure, the initial increases observed with NFV exposure seemed to decline with cumulative (>3 years) drug exposure. The association between PIs and lipid increases, particularly with LPV/RTV, is in line with results observed in adult populations and other pediatric studies.6,17,18
For both NNRTIs, an initial TC rise was observed with initial exposure, before levels began to stabilize or decrease. Almost half of this TC increase seems to be driven by HDL increases. Increased exposure to NVP was associated with larger HDL increases in this study. However, the impact of EFV on non-HDL was smaller. Combined with HDL increases seen, overall EVF may be the more cardioprotective NNRTI. This potentially beneficial HDL increase associated with NNRTIs has been seen in other pediatric5 and adult populations.30-32
As CVD is rare in children in the absence of familial hypercholesterolemia or congenital heart disease, it is difficult to know at which level interventions are appropriate. Research in pediatric cardiovascular health suggests that inflammatory disorders such as systemic lupus erythematosus represent a moderate level of risk for heart disease, but when combined with hyperlipidemia, this risk increases to a high level (ie, clinical evidence of CVD under 30 years old).27 Risk factors for atherosclerosis have been reported as early as the first decade of life.22 When considering the AAP guidelines for pharmacological intervention in pediatric hyperlipidemia, we found 2.2% of our cohort would meet borderline criteria (ie, would require intervention if 2 or more CVD risk factors are present). A smaller proportion (0.7%) would require pharmacological intervention in the absence of risk factors. However, following recommendations for management of dyslipidemia in inflammatory disorders,27 just over 10% had LDL >95 percentile, of which 60% remained elevated 1 year later. A possible explanation for lipid levels falling below the cutoff at a year is increase in age6; however, we found no association between cholesterol and age.
The patterns of blood lipids seen in this cohort suggest that once children are stabilized on a regimen for 1-2 years, if their LDL is <95th percentile (3.3 mmol/L), then the frequency of monitoring cholesterol could be reduced to yearly. Children on regimens containing boosted PIs may require more frequent monitoring.
Proposed interventions for management of HIV-associated dyslipidemia include lifestyle interventions, treatment switching, and pharmacological management.33 Dietary interventions include advice for a cardioprotective diet, for example, from the American Heart Association.34 Physical activity may also be useful for improving dyslipidemia.35 DHIVA (Dietitians working in HIV/AIDS, a specialist group of the British Dietetic Association) has developed and is currently piloting a treatment algorithm based on American Heart Association/AAP guidelines (http://www.chiva.org.uk/health/guidelines/dyslipidaemia).
Interventions, when conservative management of hyperlipidemia fails, should include treatment switching methods where possible and then pharmacological interventions. Results of PENPACT 1 show no difference between PIs and NNRTIs36 in treatment efficacy, and switches from PI to NNRTI have demonstrated improvements in TC:HDL ratios in adults37-39 and in children naive to NNRTIs.40-42 Which NNRTI would be favorable remains unclear. EFV produces lower rises in non-HDL cholesterol. However, NVP seems to produce greater increases in HDL cholesterol despite increases in non-HDL. In the event that medical intervention is needed, pravastatin does not interact with ART33,43,44and has been shown to be safe in children with familial hypercholesterolemia.45 The risk of noncompliance with ART with the additional pill burden and possible side effects of headache or abdominal discomfort with statins should also be considered.
Limitations to this study include possible channelling bias due to the treating clinician's choice of ART and knowledge of cardiovascular risk. Lipid levels may be confounded with changes that would be expected with increasing age; however, age was a variable in multivariate analysis. The age of this study population was young, mean of 6.6 years at baseline; older study populations are needed. We used nonfasting samples that may overestimate the rate of hyperlipidemia. However, a recent report of postprandial LDL levels over time does not show significant variation either by direct analysis or when calculated by Friedewald equation.46 Last, we have no information regarding lipodystrophy, pubertal status, other cardiovascular risk factors, dietary intake, or conservative management interventions. However, children with raised cholesterol levels or elevated BMI are referred to the dietitian.
We have found evidence of an association between specific ARV drugs, in particular the PIs with LPV/RTV showing greater detrimental lipid changes than NFV in a pediatric population. NNRTIs were associated with an increase in cholesterols, but this is in part due to a rise in protective HDL. Only 0.7% of the children considered met the AAP guidelines for pharmacological intervention during an average follow-up period of nearly 5 years. However, using lower cutoff guidelines accounting for the increased risk of inflammation associated with HIV infection, up to 10% may require intervention. Measuring surrogate CVD markers such as lipids over time is required, but monitoring frequency could be adjusted based on the individual child's risk. Clinical trials are required to develop and test intervention strategies to protect against CVD in children born with HIV, growing into adult life.
1. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med
2. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med
3. Ren Z, Yao Q, Chen C. HIV-1 envelope glycoprotein 120 increases intercellular adhesion molecule-1 expression by human endothelial cells. Lab Invest
4. Kaplan RC, Kingsley LA, Sharrett AR, et al. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis
5. Rhoads MP, Smith CJ, Tudor-Williams G, et al. Effects of highly active antiretroviral therapy on paediatric metabolite levels. HIV Med
6. 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
7. 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
8. Lainka E, Oezbek S, Falck M, et al. Marked dyslipidemia in human immunodeficiency virus-infected children on protease inhibitor-containing antiretroviral therapy. Pediatrics
9. Bitnun A, Sochett E, Babyn P, et al. Serum lipids, glucose homeostasis and abdominal adipose tissue distribution in protease inhibitor-treated and naive HIV-infected children. AIDS
10. Aldamiz-Echevarria L, Pocheville I, Sanjurjo P, et al. Abnormalities in plasma fatty acid composition in human immunodeficiency virus-infected children treated with protease inhibitors. Acta Paediatr
11. 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
12. Aldrovandi GM, Lindsey JC, Jacobson DL, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and youth. AIDS
13. Cheseaux JJ, Jotterand V, Aebi C, et al. Hyperlipidemia in HIV-infected children treated with protease inhibitors: relevance for cardiovascular diseases. J Acquir Immune Defic Syndr
14. Solorzano Santos F, Gochicoa Rangel LG, Palacios Saucedo G, et al. Hypertriglyceridemia and hypercholesterolemia in human immunodeficiency virus-1-infected children treated with protease inhibitors. Arch Med Res
15. 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
16. Kim JY, Zaoutis T, Chu J, et al. Effects of highly active antiretroviral therapy (HAART) on cholesterol in HIV-1 infected children: a retrospective cohort study. Pharmacoepidemiol Drug Saf
17. Periard D, Telenti A, Sudre P, et al. Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation
18. Sullivan AK, Nelson MR. Marked hyperlipidaemia on ritonavir therapy. AIDS
19. Beregszaszi M, Dollfus C, Levine M, et al. Longitudinal evaluation and risk factors of lipodystrophy and associated metabolic changes in HIV-infected children. J Acquir Immune Defic Syndr
20. Kannel WB, Giordano M. Long-term cardiovascular risk with protease inhibitors and management of the dyslipidemia. Am J Cardiol
21. Mikhail IJ, Purdy JB, Dimock DS, et al. High rate of coronary artery abnormalities in adolescents and young adults infected with human immunodeficiency virus early in life. Pediatr Infect Dis J
22. Frontini MG, Srinivasan SR, Xu J, et al. Usefulness of childhood non-high density lipoprotein cholesterol levels versus other lipoprotein measures in predicting adult subclinical atherosclerosis: the Bogalusa Heart Study. Pediatrics
23. Gibb DM, Duong T, Tookey PA, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. BMJ
24. The SMART/INSIGHT and the D:A:D Study Groups. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients. AIDS
25. Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics
26. Daniels SR, Greer FR. Lipid screening and cardiovascular health in childhood. Pediatrics
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. American Academy of Pediatrics. National Cholesterol Education Program: Report of the expert panel on blood cholesterol levels in children and adolescents. Pediatrics
. 1992;89(pt 2):525-584.
29. Sellmeyer DE, Grunfeld C. Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev
30. Anastos K, Lu D, Shi Q, et al. Association of serum lipid levels with HIV serostatus, specific antiretroviral agents, and treatment regimens. J Acquir Immune Defic Syndr
31. Fisac C, Fumero E, Crespo M, et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS
32. van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1. PLoS Med
33. Calza L, Manfredi R, Chiodo F. Hyperlipidaemia in patients with HIV-1 infection receiving highly active antiretroviral therapy: epidemiology, pathogenesis, clinical course and management. Int J Antimicrob Agents
34. Gidding SS, Dennison BA, Birch LL, et al. Dietary recommendations for children and adolescents: a guide for practitioners. Pediatrics
35. Miller TL, Somarriba G, Kinnamon DD, et al. The effect of a structured exercise program on nutrition and fitness outcomes in human immunodeficiency virus-infected children. AIDS Res Hum Retroviruses
36. PENPACT1 Protocol Team; PACTG/IMPAACT/NICHD: Brouwers P, Costello D, Ferguson E, Fiscus S, Hodge J, Hughes M, Jennings C, Melvin A, (Co-Chair) RMC-C, Mofenson L, Warshaw M, Smith E, Spector S, Stiehm E, Toye M, Yogev R. A phase II/III randomised, open-label trial of combination antiretroviral regimens and treatment-switching strategiesin HIV-1-infected antiretroviral naïve children. XVIII International AIDS Conference in Vienna; July 2010.
37. Martinez E, Conget I, Lozano L, et al. Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS
38. Estrada V, De Villar NG, Larrad MT, et al. Long-term metabolic consequences of switching from protease inhibitors to efavirenz in therapy for human immunodeficiency virus-infected patients with lipoatrophy. Clin Infect Dis
39. 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
40. Gonzalez-Tome MI, Amador JT, Pena MJ, et al. Outcome of protease inhibitor substitution with nevirapine in HIV-1 infected children. BMC Infect Dis
41. 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
42. Vigano A, Aldrovandi GM, Giacomet V, et al. Improvement in dyslipidaemia after switching stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children. Antivir Ther
43. Williams D, Feely J. Pharmacokinetic-pharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet
44. Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet
45. Wiegman A, Hutten BA, de Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA
46. Mora S, Rifai N, Buring JE, et al. Comparison of LDL cholesterol concentrations by Friedewald calculation and direct measurement in relation to cardiovascular events in 27,331 women. Clin Chem
47. Tien PC, Benson C, Zolopa AR, et al. The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol
Keywords:© 2011 Lippincott Williams & Wilkins, Inc.
child; HIV; antiretroviral therapy; hypercholesterolemia; treatment switch; statins