JAIDS Journal of Acquired Immune Deficiency Syndromes:
Cardiovascular Disease Risk in Pediatric HIV: The Need for Population-Specific Guidelines
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.
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.
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