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. Author manuscript; available in PMC: 2018 Jan 1.
Published in final edited form as: Pediatr Infect Dis J. 2017 Jan;36(1):53–60. doi: 10.1097/INF.0000000000001352

Safety and Efficacy of Atorvastatin in Human Immunodeficiency Virus-Infected Children, Adolescents and Young Adults with Hyperlipidemia

Ann J Melvin 1, Grace Montepiedra 2, Lisa Aaron 2, William A Meyer III 3, Hans M Spiegel 4, William Borkowsky 5, Mark J Abzug 6, Brookie M Best 7, Marilyn J Crain 8, Peggy R Borum 9, Bobbie Graham 10, Patricia Anthony 11, Katherine Shin 12, George K Siberry 13, for the P1063 Study Team
PMCID: PMC5154931  NIHMSID: NIHMS819734  PMID: 27749649

Abstract

Background

HIV-infected children receiving antiretroviral therapy (ART) have increased prevalence of hyperlipidemia and risk factors for cardiovascular disease. No studies have investigated the efficacy and safety of statins in this population.

Methods

HIV-infected youth aged 10 - < 24 years on stable ART with low-density lipoprotein-cholesterol (LDL-C) ≥130 mg/dL for ≥ 6 months initiated atorvastatin 10mg once daily. Atorvastatin was increased to 20mg if LDL-C efficacy criteria (LDL-C < 110 mg/dL or decreased ≥30% from baseline) were not met at week 4. Primary outcomes were safety and efficacy.

Results

Twenty-eight youth initiated atorvastatin; 7 were 10 - 15 years and 21 were 15 - 24 years. Mean baseline LDL-C was 161mg/dL (sd 19mg/dL). Efficacy criteria were met at week 4 by 17/27(63%). Atorvastatin was increased to 20mg in 10 participants. Mean LDL-C decreased from baseline by 30% (90% CI: 26%, 35%) at week 4, 28% (90% CI: 23%, 33%) at week 24, and 26% (90% CI: 20%, 33%) at week 48. LDL-C was less than 110 mg/dL in 44% at week 4, 42% at week 12, and 46% at weeks 24 and 48.Total cholesterol (TC), non-high-density lipoprotein (non-HDL)-C and apolipoprotein B (ApoB) decreased significantly, but IL-6 and high-sensitivity C-reactive protein did not. Two participants in the younger age group discontinued study for toxicities possibly related to atorvastatin.

Conclusions

Atorvastatin lowered TC, LDL-C, non-HDL-C and ApoB in HIV-infected youth with ART-associated hyperlipidemia. Atorvastatin could be considered for HIV-infected children with hyperlipidemia, but safety monitoring is important particularly in younger children.

Keywords: HIV, children, atorvastatin

Background

Accumulating evidence suggests that adults with human immunodeficiency virus (HIV) infection are at increased risk for early cardiovascular disease1-5. Statins have proven efficacy and safety for adults with HIV who meet criteria for treatment6

Guidelines from the National Heart, Lung and Blood Institute and the American Academy of Pediatrics7 provide recommendations for the use of statins in children and adolescents with hypercholesterolemia. HIV infection is one of the risk factors to be taken into account when determining the low-density lipoprotein cholesterol (LDL-C) level at which drug therapy should be considered. Elevated cholesterol levels are common in ART-treated HIV-infected children with greatest increases associated with use of protease inhibitors8-13; however, there are no clear recommendations for management of ART-associated hyperlipidemia in children and adolescents.

Atorvastatin is US Food and Drug Administration (FDA)-labeled for treatment of heterozygous familial hypercholesterolemia in adolescents and children as young as 10 years 14-18, but no studies of atorvastatin (or any statin) treatment have been reported in HIV-infected children and adolescents. The purpose of this study was to investigate the safety and efficacy of daily atorvastatin in HIV-infected children, adolescents and young adults with elevated LDL-C.

Methods

Participants

Subjects were HIV-infected children, adolescents and young adults aged 10 to < 24 years on stable antiretroviral regimens for at least six months prior to study entry (hereafter, the term “youth” will be used to indicate the entire age range). Participation required direct LDL-C ≥ 130 mg/dL at study screening and at least twice over the previous 6 months (fasted calculated LDL-C allowed for these measurements), with documented attempts at modifying diet and other risk factors for at least 3 months. Other inclusion criteria included: CD4% ≥ 15%, HIV-1 RNA ≤ 10,000 copies/mL and Tanner stage ≥ 2. Participants were excluded for laboratory values above grade 2 toxicity criteria (above grade 0 for liver enzymes and creatine kinase (CK)), past myopathy or neuromuscular disorder, chronic myositis, hepatitis, diabetes mellitus (DM), use of contraindicated medications, chemotherapy and pregnancy. The protocol was approved by the institutional review board at each participating site and all guardians and children, as appropriate, gave written consent.

Study Design

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1063 was a phase I/II, single-arm safety and efficacy study of atorvastatin (Lipitor®) for the treatment of elevated LDL cholesterol in HIV-infected youth. Enrollment was stratified by age group, with a target of 20 participants 10 - < 15 years of age and 20 ≥ 15 - < 24 years of age. Enrollment was discontinued prematurely for administrative reasons after 28 participants enrolled. Participants started on atorvastatin at 10 mg once daily. If the participant's direct LDL-C was either reduced to <110 mg/dL or declined by ≥30% from baseline at week 4, the participant continued on the 10 mg daily dose. Otherwise, the participant's dose was increased to 20 mg once daily starting from week 8, provided that the participant did not develop any atorvastatin-related Grade ≥ 3 toxicity (or alanine amino-transferase (ALT) or aspartate amino-transferase (AST) ≥ Grade 2) by week 8. Study duration was 48 weeks.

Laboratory Assessments

Fasting (minimum 8 hours) sera were obtained at screening, entry, and weeks 4, 12, 24 and 48. Sera in serum separator tubes were allowed to clot for 30 minutes at ambient temperature and subsequently centrifuged within 1 hour. Aliquots were preserved at ≤ -70°C within 8 hours of collection.

Ultrafrozen sera aliquots were shipped to Quest Diagnostics, Baltimore for real-time determination of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), directly measured LDL-C and triglycerides which were assayed using commercially available FDA-cleared methods 19-22. Additional aliquots were stored at ≤ -70°C for end of study batch testing of specialty chemistry analytes. Apolipoproteins A1 and B and high sensitivity interleukin-6 (IL-6) were measured at Quest Diagnostics Nichols Institute21,23,24. High sensitivity C-reactive protein (hsCRP) was tested with an FDA-cleared, particle enhanced immunonephelometric assay at Quest Diagnostics, Baltimore23,25.

Adherence assessment

Adherence to ART and atorvastatin for the prior 3 days and for the last month was assessed using a standardized questionnaire at each study visit. Adherence was defined as excellent if the participants reported no missed doses in the previous 3 days.

Primary Efficacy Endpoint

Baseline LDL-C was defined as the mean of the direct LDL-C values at screening and entry. Subjects were identified as having an efficacious outcome if their LDL-C was < 110 mg/dL or if their LDL-C decreased by at least 30% from baseline at a given visit.

Toxicity Management

Safety labs were measured at each study visit. The study team reviewed all laboratory values ≥ Grade 2 for relatedness to atorvastatin and all adverse events were reviewed by the IMPAACT Study Monitoring Committee. Safety endpoints included any Grade ≥3 toxicity; AST and ALT ≥ Grade 2; total amylase and direct bilirubin ≥ 2 times the upper limit of normal (ULN).

Statistical Analyses

Baseline values for lipids and inflammatory markers were calculated by taking the mean of screening and entry (week 0) values. Intent-to-treat analysis of efficacy included all participants who started study drug; those without a fasting direct LDL-C at the relevant follow-up week were considered failures. The as-treated analysis of efficacy included those participants who were on study treatment and had direct LDL-C data available at the specified follow-up week. Exact 90% confidence intervals for proportions were computed based on the binomial distribution. Mean percent change from baseline and corresponding 90% confidence intervals were computed for normally distributed data, and median percent change from baseline and corresponding 90% confidence intervals were computed for highly skewed data. The use of a 90% level of confidence reflects the intent of the study to produce pilot estimates of safety and efficacy outcomes in this population for descriptive purposes rather than to conduct hypothesis testing. Statistical analysis and graphics were performed using SAS 9.4 (SAS Institute, Cary NC).

Results

Baseline Characteristics of Participants

All 28 participants initiated study treatment within three days of enrollment. The median age was 17 years (range 10-23), 68% of participants were female, and 64% were black non-Hispanic (Table 1). Median body mass index was 22.7 kg/m2. Median CD4 percent was 36% at screening. Plasma HIV-1 RNA was below the lower limit of quantitation of the local site assay in 71% of participants. ART regimens at study entry contained at least one non-nucleoside reverse transcriptase inhibitor (NNRTI) for 32% of participants and at least one protease inhibitor (PI) for 79% of participants.

Table 1. Baseline Characteristics of N=28 HIV-Infected Children, Adolescents and Young Adults with Elevated LDL Cholesterol.

Characteristic Number (%)
Age at study entry (years) Mean (s.d.) 17 (4)
Min, Max 10, 23
Median 17
Age Group ≥10 to <15 years old 7 (25%)
15 to <19 years old 12 (43%)
19 to <24 years old 9 (32%)
Sex Male 9 (32%)
Female 19 (68%)
Race/Ethnicity White Non-Hispanic 4 (14%)
Black Non-Hispanic 18 (64%)
Hispanic (Regardless of Race) 5 (18%)
Asian, Pacific Islander 1 (4%)
BMI (kg/m2) at entry1 Mean (s.d.) 25.6 (9.5)
Min, Max 14.7, 55.8
Median 22.7
CD4 Percent at screening 15 to <25% 2 (7%)
≥25% 26 (93%)
HIV-1 RNA (copies/mL)2 ≥LLQ 8 (29%)
<LLQ 20 (71%)
ARV regimen at entry At least 1 PI3 and at least 1 NNRTI 5 (18%)
At least 1 PI and no NNRTI 17 (61%)
At least 1 NNRTI and no PI 4 (14%)
Other ARV regimen 2 (7%)
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1

Screening data were used when entry data were unavailable; BMI was missing for 1 participant at both screening and entry.

2

LLQ = Lower limit of quantification of assay

3

All PIs were boosted except for one participant

Application of Study Algorithm and Efficacy Endpoints

Seventeen of the 28 participants (61%) met the efficacy endpoint at week 4 (Figure 1) and were eligible to remain on the starting dose of 10 mg until they completed the study. Fifteen remained on the starting dose until week 48. One participant received an unintended dose increase to 20 mg from week 8 to week 48. Another participant experienced a toxicity potentially related to atorvastatin at week 6 and was taken off study treatment. The latter participant had a rebound in LDL-C at week 12 and had missing lipid evaluations for the remainder of the study. Ten of the 28 study participants (36%) did not meet the week 4 efficacy endpoint, and all except one of these received the protocol-prescribed dose increase to 20 mg from week 8 until week 48. The participant who was not dose-escalated (and continued on 10 mg until week 48) entered the study with a Grade 2 rash that worsened to a Grade 3 by week 4, prompting the family to refuse the dose increase. The rash ultimately resolved and was deemed to be unrelated to atorvastatin. Finally, one participant had unknown LDL-C at week 4, was non-adherent to study visits and medication, and was taken off study treatment at week 9 and off study at week 47. Mean baseline LDL-C was similar between those who met efficacy criteria at week 4 (161 mg/dL, SD 17 mg/dL) and those who required dose escalation (163 mg/dL, SD 24 md/dL).

Figure 1. Study profile.

Figure 1

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LDL-C = low density lipoprotein cholesterol.

Based on an intent-to-treat analysis with all 28 participants who started study medication included in the denominator, 61% (90% CI: 44%, 76%) met efficacy criteria at week 4, 46% (90% CI: 30%, 63%) at week 12, 57% (90% CI: 40%, 73%) at week 24 and 54% (90% CI: 37%, 70%) at week 48. Among those participants who were on study treatment and had LDL-C data available at the specified time point, 63% (90% CI: 45%, 78%) met efficacy criteria at week 4, 50% (90% CI: 33%, 67%) at week 12, 62% (90% CI: 44%, 77%) at week 24, and 58% (90 % CI: 40%, 74%) at week 48.

Changes in Lipid Concentrations

Baseline mean direct LDL-C of the 28 participants and decreases by study week are detailed in Table 2 and Figure 2. The percentage of participants with LDL-C less than 110 mg/dL was 44% (90% CI: 28%, 62%) at week 4, 42% (90% CI: 26%, 60%) at week 12, and 46% (90% CI: 29%, 64%) at weeks 24 and 48. LDL-C concentrations after baseline were fairly stable over the 48 weeks of the study for the majority of participants, although some individuals had noticeable variation in their LDL-C concentrations at different study visits.

Table 2. Lipid and lipoprotein concentrations (in mg/dL) before atorvastatin treatment and changes from baseline during atorvastatin treatment.

Baseline Week 4 Week 12 Week 24 Week 48
(N=28) (N=27) (N=26) (N=26) (N=26)
LDL cholesterol (mg/dL)1 Mean (s.d.) 161 (19) 112 (21) 117 (30) 116 (27) 117 (27)
Median (Min, Max) 162 (133, 207) 113 (74, 165) 114 (68, 179) 110 (84, 173) 115 (67, 164)
Mean % change (90% CI) -30.3 (-34.6, -26.1) -27.3 (-33.3, -21.4) -28.0 (-32.7, -23.4) -26.4 (-33.0, -19.7)
HDL cholesterol (mg/dL) Mean (s.d.) 51 (13) 51 (11) 52 (15) 52 (14) 52 (13)
Median (Min, Max) 50 (31, 77) 49 (35, 80) 50 (25, 88) 48 (36, 90) 53 (30, 84)
Mean % change (90% CI) 1.8 (-2.5, 6.1) 2.2 (-1.4, 5.8) 3.0 (-3.1, 9.1) 4.2 (-3.5, 11.9)
Total Cholesterol (mg/dL) Mean (s.d.) 237 (27) 182 (27) 186 (34) 184 (32) 185 (29)
Median (Min, Max) 240 (179, 285) 178 (135, 235) 187 (113, 249) 176 (142, 261) 185 (120, 248)
Mean % change (90% CI) -23.8 (-26.8, -20.8) -21.8 (-25.8, -17.9) -22.5 (-26.0, -19.0) -21.5 (-26.4, -16.6)
Non-HDL cholesterol (mg/dL) Mean (s.d.) 187 (26) 130 (27) 133 (29) 133 (29) 133 (30)
Median (Min, Max) 186 (136, 250) 129 (86, 185) 132 (79, 181) 124 (99, 192) 130 (74, 197)
Mean % change (90% CI) -30.6 (-34.3, -26.9) -28.4 (-32.9, -23.9) -28.9 (-33.0, -24.8) -28.0 (-34.0, -22.1)
Triglycerides (mg/dL) Mean (s.d.) 160 (89) 136 (64) 143 (82) 130 (50) 142 (103)
Median (Min, Max) 124 (61, 387) 121 (38, 272) 126 (32, 390) 121 (57, 250) 111 (44, 566)
Mean % change (90% CI) -9.5 (-20.4, 1.4) -12.2 (-19.3, -5.1) -11.3 (-22.8, 0.3) -12.6 (-22.5, -2.7)
Baseline Week 12 Week 24 Week 48
(N=27) (N=24) (N=23) (N=24)
Apolipoprotein A1 (mg/dL) Mean (s.d.) 140 (22) N/A 142 (28) 143 (22) 142 (22)
Median (Min, Max) 142 (91, 195) 139 (79, 198) 141 (101, 206) 146 (104, 172)
Mean % change (90% CI) 0.8 (-3.2, 4.8) 2.4 (-2.6, 7.5) 0.3 (-4.8, 5.4)
Apolipoprotein B (mg/dL) Mean (s.d.) 127 (20) N/A 92 (19) 94 (19) 95 (23)
Median (Min, Max) 128 (88, 176) 95 (58, 127) 87 (68, 131) 90 (58, 135)
Mean % change (90% CI) -27.2 (-32.1, -22.4) -25.1 (-29.6, -20.7) -23.8 (-30.5, -17.2)
Apolipoprotein B/A1 Ratio Mean (s.d.) 0.93 (0.22) N/A 0.66 (0.15) 0.67 (0.17) 0.69 (0.21)
Median (Min, Max) 0.92 (0.61, 1.56) 0.70 (0.34, 0.90) 0.67 (0.43, 1.05) 0.65 (0.42, 1.29)
Mean % change (90% CI) -27.3 (-32.3, -22.3) -25.6 (-31.5, -19.7) -23.5 (-30.1, -16.9)
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1

Primary efficacy measure s.d.= standard deviation CI= confidence interval

Figure 2.

Figure 2

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Mean percent change in lipid and lipoprotein concentrations from baseline during atorvastatin treatment. Error bars show 90% confidence intervals. TC= total cholesterol, LDL-C = low density lipoprotein cholesterol, HDL-C= high density lipoprotein cholesterol, TG= triglyceride, Apo A-1= apolipoprotein A-1, Apo B= apolipoprotein B

Table 2 and Figure 2 also show changes in other fasting lipids and apolipoproteins by study week. Mean HDL-C did not change substantially over the course of the study. Mean TC, mean non-HDL-C, and mean triglyceride concentrations demonstrated similar patterns of change over time, declining from baseline to week 4 and then remaining relatively constant for the remainder of follow-up.

Mean ApoA1 did not change throughout the study, while mean ApoB and ApoB/A1 declined by 27% (90% CI: 22%, 32%) from baseline to Week 12 and were steady for the remainder of study follow-up.

Safety Events and Drug Toxicity

Two participants [7%; 90% CI: 1% - 21%] discontinued study treatment due to toxicities possibly related to atorvastatin by week 48. Both participants were in the younger age group (10-<15 years old), were receiving zidovudine/lamivudine/lopinavir/ritonavir at study entry and were receiving 10mg atorvastatin. One participant had a Grade 3 creatinine elevation at week 6 with no changes in ARV regimen prior to week 6; another had Grade 4 ALT and AST elevations at the final study visit and also received a diagnosis of drug-induced hepatitis. This participant's ARV regimen had been changed to abacavir/lamivudine/atazanavir at week 24. Both participants had normal values at baseline.

Six other participants experienced non-treatment related Grade 3 events: one elevated total bilirubin level at week 8 (attributed to atazanavir); one elevated total amylase at week 35 (ibuprofen overdose); one elevated CK at week 9 (high levels of physical activity); one elevated fasting glucose level at week 3; and one non-allergic rash at week 4 (exudative pharyngitis). No other Grade 4 events and no deaths occurred.

Changes in Markers of Inflammation

Descriptive statistics for serum IL-6 and hs-CRP and their percent change over time are shown in Table 3. Median IL-6 was 1.66 pg/mL at baseline and fluctuated over time with no clear trend. Median percent change in IL-6 was also variable, and the corresponding confidence intervals were wide. Median hs-CRP was 1.20 mg/L at baseline and 1.00 mg/L at week 12 before declining to 0.50 mg/mL at week 24 and 0.60 mg/L at week 48; however, the ranges of hs-CRP values at all weeks were relatively large.

Table 3. Absolute inflammatory marker concentrations before atorvastatin treatment and changes during atorvastatin treatment.

Baseline Week 12 Week 24 Week 48
IL-6 (pg/mL) N 27 24 23 24
Mean (s.d.) 1.83 (1.53) 2.27 (1.71) 1.53 (1.09) 2.63 (4.92)
Median (Min, Max) 1.66 (0.47, 7.94) 1.94 (0.51, 6.97) 1.36 (0.42, 4.41) 1.15 (0.56, 24.56)
Mean % change (90% CI) 62.1 (11.6, 112.6) -1.3 (-22, 19.4) 40.2 (-6, 86.4)
Median % change (90% CI) -1 (-32, 110) -19 (-32, -5) -11.5 (-34, 46)
hs-CRP (mg/L) N 27 25 23 24
Mean (s.d.) 4.32 (5.97) 4.14 (6.18) 1.91 (3.92) 1.88 (4.05)
Median (Min, Max) 1.20 (0.20, 22.00) 1.00 (0.20, 20.50) 0.50 (0.20, 18.90) 0.60 (0.20, 19.30)
Mean % change (90% CI) 132.2 (23.5, 240.9) -9.8 (-43.3, 23.7) 20.4 (-33.8, 74.6)
Median % change (90% CI) 0 (-35, 44) -20 (-67, 0) 0 (-78, 17)
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IL-6= interleukin-6 hs-CRP= highly sensitive C-reactive protein s.d.= standard deviation CI= confidence interval

Virologic Changes

The percentage of participants with HIV-1 RNA viral load (VL) below the lower limit of quantitation was 71% at week 0, 69% at week 12, 62% at week 24, and 69% at week 48. Of those with undetectable VL at baseline and follow-up data available, 80% had undetectable VL at week 48 and 55% had undetectable VL at all study weeks. Of those with detectable virus at baseline, median plasma HIV-1 RNA concentration was low (2.5 log10 copies/mL) and unchanging over time.

Discussion

The HIV-infected youth participating in P1063 experienced a significant decline in plasma lipid concentrations after initiating atorvastatin. The overall decline in LDL-C and TC was somewhat less than that seen in children with familial hypercholesterolemia15,16 but similar to that in children with Kawasaki disease18, Type 1 diabetes26 and systemic lupus17. LDL-C and TC decreased by a mean of 39% and 31%, respectively, between baseline and 26 weeks in the 140 children randomized to atorvastatin in a placebo-controlled trial in children and adolescents with familial or severe hypercholesterolemia15. The larger decrease may have been due in part to the study design which required dose escalation if LDL-C <130 mg/dL was not achieved at 4 weeks on 10 mg of atorvastatin. In contrast, participants in P1063 did not dose escalate if their LDL-C decreased by ≥ 30% regardless of actual concentration achieved. Similarly, studies in adults have found somewhat lower responses to statins in HIV-infected vs uninfected adults27-29.

Some individuals demonstrated considerable variability in LDL-C concentrations during the study suggesting that adherence to atorvastatin may not have been as consistent as was indicated through self-report. Alternatively, dietary intake may have been variable. One participant, who changed from a boosted-PI to an unboosted-PI at week 24, had lower LDL-C at week 48. Two additional participants had ARV changes during the study period which did not appear to affect their LDL-C.

In addition to LDL-C, ApoB, non-HDL-C and ApoB/Apo A-1 ratio decreased significantly from baseline to week 48. ApoB, a measure of total atherogenic particle number, and non-HDL-C, which includes very low density lipoprotein cholesterol as well as LDL-C, are additional measures of cardiovascular disease risk30-33. Several studies have shown ApoB concentrations to be a better predictor of cardiovascular disease risk than LDL-C concentrations in HIV-uninfected adults treated with statins34-36.

The association between childhood risk factors including LDL-C37,38and adult cardiovascular disease has been demonstrated through longitudinal epidemiologic studies37-39. Similarly, evidence is accumulating for increased cardiovascular risk in HIV-infected children and adolescents, including elevated cholesterol concentrations particularly in those on PI-based ART8,9,12,13 and increased Pathobiological Determinants of Atherosclerosis in Youth scores40. Increased carotid artery intima-media thickness (CIMT) has been demonstrated in some pediatric HIV-infected cohorts41-43 but not others44. The finding of increased risk of development of coronary heart disease in young HIV infected adults between the ages of 18-24 years45 highlights the potential risk for early cardiovascular disease even in children with perinatal HIV infection.

While no studies directly demonstrate a decrease in mortality related to cardiovascular disease in HIV-infected adults treated with statins, there is evidence that statins decrease subclinical cardiovascular disease: including decreased CIMT46, improved endothelial function47, decreases in markers of vascular inflammation48,49 and decreased non-calcified coronary artery plaque volume50. Statin therapy reduces risk for cardiovascular disease by effectively decreasing both cholesterol concentrations and chronic inflammation. While the immune mechanisms resulting in increased atherosclerosis are complex, hs-CRP has been shown to be a relevant surrogate marker for immune activation and is a significant independent risk factor for myocardial infarction and peripheral vascular disease51-53. Statins lower hs-CRP concentrations in adults and the clinical efficacy in reducing cardiovascular disease is independently related to the ability of statins to reduce both blood lipid concentrations and hs-CRP54-57. Both elevated hs-CRP and HIV infection were found to be independent risk factors for risk of acute myocardial infarction in adults58 and increased hs-CRP concentrations have been associated with increased CIMT in HIV-infected adults59 and children60. Statin use resulted in decreased hs-CRP in HIV-infected adults in some studies61,62 but not others63. Although both hs-CRP and IL-6 concentrations appeared to decrease in this study after initiation of atorvastatin, the variability was high for both analytes. As IL-6 and hs-CRP are acute phase reactants and participants were not required to be free of minor symptoms such as upper respiratory tract infections, the concentrations may have been affected by the clinical status of the participant at the time of the study visits. Therefore this study suggests, but cannot confirm, a decrease in inflammatory markers after initiation of atorvastatin treatment in HIV-infected youth.

Many of the statins currently in use are metabolized by cytochrome P450 (CYP) 3A4 enzymes; therefore the risk for drug interactions with PIs is significant. Simvastatin and lovastatin are contraindicated with PIs due to significantly increased statin levels64,65. Atorvastatin concentrations are affected less by concomitant PI administration65 and atorvastatin has been used safely in HIV-infected adults6,66. Atorvastatin should not be co-administered with tipranavir and the dose should not exceed 20 mg when co-administered with darunavir, fosamprenavir/ritonavir or saquinavir/ritonavir65,67. In contrast, administration of atorvastatin does not affect PI drug concentrations64,65. Currently, atorvastatin is FDA-labeled for use in children down to age 10 years with heterozygous familial hyperlipidemias 68.

A systematic review of the literature on the safety and tolerability of atorvastatin found a low incidence of elevated liver enzymes, CK and myalgias, with no clear dose-dependency69. Serious muscle-related side effects have been rare across clinical studies. While myalgia occurred in close to 5% of participants, the rate of persistent increase in CK (>10xULN) ranged from 0.1% to 0.4%, with few cases of rhabdomyolysis 69-71. Drug-induced rhabdomyolysis after the concomitant use of boosted PI, macrolide antibiotic therapy (lopinavir/ritonavir together with clarithromycin) and atorvastatin has been reported72. There have been reports of increased risk for type 2 DM in adults treated with statins. The increased risk across all statins is low73 and largely associated with high-dose statin therapy74. No adolescents or children were included in these studies.

A meta-analysis of statin use in children showed an overall favorable safety profile similar to that in adults, with increased risk of adverse events mainly with higher doses and co-administration of interacting drugs metabolized by the CYP system. Five studies reported on elevations of AST, ALT, and CK, with no substantial elevations in 2 studies for AST and 3 studies for ALT and CK75. However, due to the limited sample size and short study duration, the authors drew no definite conclusions on liver- and muscle-related adverse effects and recommended monitoring muscle and liver safety markers in pediatric patients. Treatment-related hepatic (1 possibly related) and muscle (0) toxicity were uncommon in our study despite use of PIs in 79% of participants at study entry, consistent with the reported safety of statins in adults with HIV6. Renal toxicity has not been reported for atorvastatin and only one report of creatinine increase with concomitant uric acid serum level elevation is in the literature76.

Conclusion

Management options for TC and/or LDL-C elevations in HIV-infected children include life-style and dietary changes, or switching to ARVs less likely to elevate lipid concentrations77-81. If lipid concentrations do not improve with these interventions or for individuals in whom such interventions are not feasible, our data suggest that treatment with atorvastatin appears to be safe and effective for HIV-infected youth on ART.

Acknowledgments

Atorvastatin (Lipitor®) for this study was provided by Pfizer, Inc. We gratefully acknowledge the contributions of the site investigators and site staff who conducted the P1063 study:

Texas Children's Hospital: Chivon McMullen-Jackson, RN, BSN, CCRP, Norma Cooper, RN, BSN, MS, Mary Paul, MD, William Shearer, MD, PhD; Lurie Children's Hospital of Chicago: Ruth Williams, RN, Lynn Heald, PNP, Margaret Ann Sanders, MPH, Ram Yogev, MD; University of Miami Pediatric Perinatal HIV/AIDS: Charles D. Mitchell, MD, Gwendolyn B. Scott, MD, Monica Stone, MD, Patricia Bryan, RN, BS, MPH; Metropolitan Hospital: Mahrukh Bamji, MD, Santa Paul, MD; Boston Medical Center Pediatric HIV Program: Ellen R Cooper MD, Diana Clarke PharmD, Deb McLaud, RN, C Moloney, RN, PNP, MEd; New York University: Nagamah Deygoo, MS, Siham Akleh, RN, Aditya Kaul, MD, Sulachni Chandwani MD; University of South Florida – Tampa: Carina A. Rodriguez, MD, Patricia J. Emmanuel, MD, Denise Casey, RN, Elizabeth Enriquez-Bruce, MD; University of Colorado School of Medicine and Children's Hospital Colorado: Suzanne Paul, BSN, MSN, FNP-C, Hannah Bernath, MPH, Jason Child PharmD, Jenna Wallace, MSW, CCRP; Tulane University: Margarita Silio, MD, Thomas Alchediak, MD, Russell Van Dyke, MD; Bronx-Lebanon Hospital: Mary Elizabeth Vachon, MPH, Ana Maria Emeh, MD, Murli Udharam Purswani, MD; St Jude's Children's Hospital: Nehali Patel, MD, Sandra Boyd, PNP, Thomas Wride, MS, Aditya Gaur, MD.

Source of Funding: Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), and Contract No. HHSN272200800014C, with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Footnotes

Conflicts of Interest: No authors report conflicts of interest.

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