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Cardiovascular Disease Risk in Pediatric HIV: The Need for Population-Specific Guidelines/for HIV-infected children
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Download the PDF here
Download the PDF here
Ross, Allison C MD*; McComsey, Grace A MD
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
JAIDS Journal of Acquired Immune Deficiency Syndromes:
15 August 2011
"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."
"there are no published guidelines about what lipid levels should prompt pharmacologic intervention in HIV-infected children. As a likely consequence, only a small percentage of children initiated statins after developing hypercholesterolemia in our study, and the median time to initiation of treatment was 2.5 years after development of hypercholesterolemia."
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.
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Effect of Specific ART Drugs on Lipid Changes and the Need for Lipid Management in Children With HIV
"Clinical trials are required to develop and test intervention strategies to protect against CVD in children born with HIV, growing into adult life."
Rhoads, Margaret P BA, MBBS*; Lanigan, Julie RD; Smith, Colette J PhD; Lyall, E G Hermione MBBS, MD
JAIDS Journal of Acquired Immune Deficiency Syndromes:
15 August 2011 - Volume 57
From the *Imperial College London, London, United Kingdom; UCL Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom; Research Department of Infection and Population Health, UCL Medical School, London, United Kingdom; and Imperial College Health Care Trust, St. Mary's Hospital Campus, London, United Kingdom.
Abstract
Background: We investigated the effects of individual antiretrovirals on lipids in HIV-infected children and the proportion potentially eligible for dietary or pharmacologic intervention.
Methods: St Mary's and Great Ormond Street Hospital's, London, United Kingdom, patients between 1995 and 2007 were included. Associations between lipids (millimoles per liter) and specific antiretroviral therapy were assessed using mixed-effects models adjusted for confounders. Children eligible for lipid-lowering management were assessed according to American Academy of Pediatric criteria [low-density lipoprotein (LDL) > 190 mg/dL or 4.9 mmol/L for children with no known cardiovascular disease risk factors or LDL > 160 mg/dL or 4.1 mmol/L for children with 2 or more cardiovascular disease risk factors].
Results: Four hundred forty-nine children had median 4.5-year follow-up. On average, antiretroviral therapy-naive children had normal lipids except for low high-density lipoprotein cholesterol (HDL) (median 0.8). All cholesterol subsets were elevated for the 4 drugs assessed. Protease inhibitors had greater rises in total cholesterol with the maximal non-HDL rise for lopinavir/ritonavir at 4+ years of exposure, 0.8 (0.57-1.03). The nonnucleoside reverse transcriptase inhibitors also raised non-HDL, but this was associated with additional clinically significant increases in HDL. Nevirapine raised non-HDL by 0.38 (0.09-0.31) at 2-3 years and HDL by 0.34 (0.28-0.41). Efavirenz raised non-HDL by 0.2 (0.09-0.31) and HDL by 0.12 (0.08-0.17) at 1 year. Ten percent had LDL above the 95th percentile, but only 3 met the 4.9 cutoff for pharmacologic intervention.
Conclusions: Intervention strategies (dietary and exercise advice, treatment switching, and pharmacotherapy) are required for persistent hyperlipidemia and should be assessed in randomized control trials.
INTRODUCTION
As HIV-infected children are now living into adulthood, there are increasing concerns regarding their long-term cardiovascular health.1 The etiology of cardiovascular disease (CVD) in this population may be driven by endothelial inflammation2,3 and traditional risk factors, including dyslipidemia.4 Treatment with antiretroviral therapy (ART) is associated with hypercholesterolemia, a risk factor for coronary heart disease (Tien 2006). Although both nonnucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitor (PI) classes are implicated,5,6 the greatest effects are reported with PI use.6-16,20 The PI of greatest concern is ritonavir especially when used as a booster.6,17,18 Similar effects are reported in children,6-16,19 which is particularly concerning, as children will receive treatment for a large proportion of their life.
CVD is rare in young children, and no HIV positive pediatric myocardial infarctions have been reported. However, recent reports suggest that young adults perinatally infected with HIV have high rates of coronary artery abnormalities, suggesting possible early atherosclerosis.21 Surrogate markers, such as lipids, are often used to assess CVD risk. Although the long-term sequelae of dyslipidemia in HIV-infected children are unknown, their total cholesterol (TC) levels are reported to be similar for children with heterozygous familial hypercholesterolemia, who are at increased risk of premature atherosclerotic disease.5,13
Studies report a prevalence of TC above 5.2 mmol/L (95th percentile) in 13%-27% of ART-treated children,11 many of whom experience a rise in TC from their pretreatment value.5,13,15 Typically, high-density lipoprotein (HDL), the cardioprotective cholesterol, is low in HIV-infected individuals but normalizes after starting highly active antiretroviral therapy that may be beneficial.5
The immediate benefits of ART for survival far outweigh the increased risk of CVD in later part of life. However, prevention of premature CVD is an important consideration in the management of HIV-infected children. Little is known of the specific effects of individual drugs, and although there is clear evidence to support an adverse effect of PI on the lipid profile, evidence informing treatment changes is scarce. Two large longitudinal studies have attempted to look at the effects of individual drug and class effects of antiretroviral (ARV); however, both studies have focused on TC levels.6,16 Pediatric guidelines for the management of hyperlipidemia focus on low-density lipoprotein cholesterol (LDL), and therefore, we proposed to study the association between cholesterol subfractions and commonly used individual ARTs. The aim of this study was to investigate the association of HIV viral load (VL), CD4 count, and individual ARV drugs with changes in the lipid profile of infected children. A secondary aim was to identify the number in need of hyperlipidemia management.
DISCUSSION
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.
CONCLUSIONS
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.
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JAIDS Journal of Acquired Immune Deficiency Syndromes:
15 August 2011 - Volume 57
Clinical Management and Follow-up of Hypercholesterolemia Among Perinatally HIV-Infected Children Enrolled in the PACTG 219C Study
Jacobson, Denise L PhD, MPH*; Williams, Paige PhD; Tassiopoulos, Katherine DSc, MPH; Melvin, Ann MD, MPH; Hazra, Rohan MD; Farley, John MD, MPH
Abstract
Background: Hypercholesterolemia is common in perinatally HIV-infected (HIV+) children, but little is known about the clinical course and management in this population.
Methods: We studied HIV+ children in a multisite prospective cohort study (Pediatric AIDS Clinical Trials Group 219C) and considered follow-up for 2 years after development of hypercholesterolemia. We estimated the time and factors associated with resolution of hypercholesterolemia and described changes in antiretroviral regimen and use of lipid-lowering medications. We defined incident hypercholesterolemia as entry total cholesterol (cholesterol) <220 mg/dL and 2 subsequent consecutive cholesterol ≥220 mg/dL and defined resolution of hypercholesterolemia as 2 consecutive cholesterol <200 mg/dL after incident hypercholesterolemia.
Results: Among 240 incident hypercholesterolemia cases, 81 (34%) had resolution to normal cholesterol within 2 years of follow-up (median follow-up = 1.9 years). The median age of cases was 10.3 years with 54% non-Hispanic black and 53% male. Resolution to normal cholesterol was more likely in children who changed antiretroviral regimen (adjusted hazard ratio = 2.37, 95% confidence interval: 1.45 to 3.88) and who were 13 years and older (aHR = 2.39, 95% confidence interval: 1.33 to 4.27). Types of regimen changes varied greatly, and 15 children began statins.
Conclusion: The majority of children who develop hypercholesterolemia maintain elevated levels over time, potentially placing them at risk for premature cardiovascular morbidity.
INTRODUCTION
Dyslipidemia is commonly observed in HIV-infected adults and children. Studies in adults show that lipid abnormalities occur early in HIV infection before initiation of antiretroviral therapy (ART) and are characterized by low levels of total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C).1-4 Elevated triglycerides and very-low-density lipoprotein cholesterol are observed later, especially in those with more advanced disease.5 In a study of adult male seroconverters, total-C and LDL-C increased moderately soon after initiation of highly active antiretroviral therapy and many subsequently developed elevation of total-C and LDL-C with a low HDL-C.4 In other studies, initial improvements in total-C and LDL-C after initiation of antiretroviral (ARV) coincide with restoration of health and a decrease in HIV viral load.1-3
The hyperlipidemia that is widely reported among adults6-8 and children9-14 on highly active antiretroviral therapy may be partly associated with specific classes of ARVs or individual agents. For example, several studies have reported higher total-C levels among children on protease inhibitors (PIs)10,13,15-19 and specifically with ritonavir use.10,12,18 In a longitudinal study, HIV-infected children who developed incident hypercholesterolemia were more likely to be receiving boosted or nonboosted PI.20 Children treated with a nonnucleoside reverse transcriptase inhibitor (NNRTI) also had higher total-C10,20 in 2 studies and had higher HDL-C levels15 in another study compared with those not treated with an NNRTI.
As adults and children live longer with HIV, prolonged dyslipidemia may increase the risk of atherosclerotic disease. Thus, there has been much interest in examining whether type of initial therapy or switching ARV may improve lipid profiles and still maintain viral suppression. Switch studies in adults showed improvements in cholesterol with a switch to atazanavir21-23 or raltegravir,24 from zidovudine/lamivudine to tenofovir/emtricitabine25 and from stavudine to tenofovir.26 Children who switched from PI therapy to a PI-sparing regimen containing nevirapine showed mild decreases in total-C and increases in HDL-C27 as did those who switched from PI to efavirenz.28 More studies on the effect of switching ARV are needed in children as newer ARVs, such as atazanavir and darunavir that have an improved lipid profile, are approved in children older than 6 years.
Most perinatally infected children have not been followed long enough to determine the course and long-term consequences of sustained dyslipidemia or response to therapy. In the general population, the American Academy of Pediatrics recommends change in diet and engagement in physical activity as the first step to improve lipid measurements.29 They recommend pharmacologic interventions for children with diabetes mellitus or when elevated LDL-C levels persist above a specified cutoff after dietary intervention fails to produce adequate improvement. Although several studies show efficacy of lipid-lowering agents in adults with HIV,30,31 the studies in HIV-infected children with dyslipidemia are ongoing and clearly needed to inform guidelines.
Clinical trials have investigated the association between specific ARVs and cholesterol levels in children, but little is known about the clinical management of hypercholesterolemia in practice. Tassiopoulos et al20 reported an incidence rate of hypercholesterolemia of 3.4 per 100 person-years based on data from the Pediatric AIDS Clinical Trials Group (PACTG) 219C late outcomes study. In the present analysis, based on further follow-up of the same PACTG 219C cohort, we followed children after they developed hypercholesterolemia (1) to determine whether their cholesterol levels remained elevated over time, (2) to examine factors associated with reversion to normal cholesterol over 2 years of follow-up, and (3) to describe types of changes in ARV regimens and use of lipid-lowering medications. To our knowledge, this is the first study to describe the clinical course and management of hypercholesterolemia in HIV-infected children.
DISCUSSION
The high prevalence10 and incidence of hypercholesterolemia20 previously reported in this cohort of perinatally HIV-infected children and in other studies of children9-14 raises concern about the long-term risk of cardiovascular morbidity in HIV-infected children as they age into adulthood. There is a paucity of information on the course of hypercholesterolemia over time in HIV-infected children and the factors associated with resolution of hypercholesterolemia. In this present analysis, the majority of children with incident hypercholesterolemia failed to demonstrate resolution of elevated cholesterol levels over 2 years of follow-up. The median cholesterol level decreased from 236 to 220 mg/dL in the first year, and only 20% of the children with incident hypercholesterolemia had a resolution to levels below 200 mg/dL within the first year and 35% by the second year of follow-up. Although guidelines exist for statin use in children without HIV29 and studies are now ongoing on use of lipid-lowering medications in HIV-infected children, there are no published guidelines about what lipid levels should prompt pharmacologic intervention in HIV-infected children. As a likely consequence, only a small percentage of children initiated statins after developing hypercholesterolemia in our study, and the median time to initiation of treatment was 2.5 years after development of hypercholesterolemia.
Elevated total and LDL cholesterol and lower HDL cholesterol have been associated with PIs,10,13,15-19 especially ritonavir10,12,18; NNRTIs10; and some NRTIs in HIV-infected children. Previous work in this cohort also found that children on PIs, boosted or nonboosted with ritonavir, were more likely to develop hypercholesterolemia.20 As previously mentioned, numerous switch studies were performed in adults to evaluate whether lipid levels could be improved by substituting an ARV with a less atherogenic profile, whereas a few were done in children.21-28,33 To more fully understand management of hypercholesterolemia among HIV-infected children in this study, we evaluated types of changes in ARV regimens after incident hypercholesterolemia, focusing on changes that have been studied in clinical trials. Although any change in ARV therapy after incident hypercholesterolemia was associated with decline in cholesterol to normal values, regimen changes varied greatly from single to multiple drug substitutions, showing no distinct pattern. Twenty-seven percent of children with incident hypercholesterolemia made at least 1 change in their ARV regimen over 2 years, but a few children made the type of switches that were shown to be beneficial from clinical trials conducted in adults. Of all ARV regimen changes, the most prevalent was discontinuation of efavirenz.
Change in ARV regimen was associated with a decrease in cholesterol, but it is difficult to attribute the decrease to a specific class or agent in this cohort. We lacked power to detect differences in individual medications as changes in medication ranged from single substitutions to a complete change in regimen, and the majority of patients remained on PI. In addition to evaluating the types of changes in ARV, we also studied the magnitude of change in cholesterol after changing regimen. In studies where patients were switched to tenofovir, the magnitude of effect on total cholesterol ranged from a 4 to 18 mg/dL decrease.22,25,26 Among children in our cohort who changed regimen, the average change in cholesterol was 22 mg/dL. Although regimen change was associated with decreased cholesterol, our analysis of predictors of regimen change showed that uncontrolled viral load and not hypercholesterolemia predicted change in ARV. High viral load may reflect nonadherence. Further studies are needed to understand the effect of specific regimen changes on cholesterol and to carefully control for the potential effects of disease severity, immune activation, and diet on cholesterol. In our cohort, children 13 years and older were more likely to revert to normal cholesterol. This may be partially explained by data from National Health and Nutrition Examination Survey, which showed that mean cholesterol levels peak at ages 9-11 and then decline in older children.34 Children 13 years and older were also more likely to change ARV regimen, perhaps because they have more treatment options or are less adherent to ARV, as shown previously in the 219C cohort.35 Poorer adherence could reduce exposure to deleterious effects of specific ARV, including hypercholesterolemia as shown by Tassiopoulos et al20 in the examination of risk factors for developing hypercholesterolemia in the 219C cohort.
HIV-infected adults with dyslipidemia have benefited from statin use.30,31 Clinical trials of statins in infected children began after 219C was complete. This may explain why a few children in our cohort were known to have begun statin therapy after incident hypercholesterolemia. We were unable to determine the effect of statins on cholesterol levels as we did not have enough follow-up cholesterol values after children began statins. We also did not have enough information to determine how long statins were taken and if the children were adherent. Statin use was also reported by children with prevalent hypercholesterolemia and by children who did not fit our definition of hypercholesterolemia. In addition, other lipid-lowering medications were used by children in 219C to treat other types of dyslipidemia. However, we do not have information on fasting LDL or HDL cholesterol or triglycerides to determine if these lipid components were abnormal. The present guidelines for treating dyslipidemia recommend change in diet and increase in physical activity as first-line therapy,29 which we did not collect, thus precluding assessment of compliance and benefit. Future studies will benefit from data on diet and exercise to better understand their effectiveness and provide recommendations and practice regarding dyslipidemia.
To our knowledge, a few studies have addressed management of children with hypercholesterolemia. We characterized clinical management of these children with available data and evaluated evolution of cholesterol over time and factors associated with resolution to normal levels. Future studies should monitor changes in LDL and HDL cholesterol and triglycerides over time in response to improvements in diet and exercise, newer ARV medications, and lipid-lowering medications. It is important to understand the long-term risk of cardiovascular disease among HIV-infected children as they progress to adulthood to develop safe preventive measures.
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