Background: Both HIV infection and antiretroviral therapy are associated with dyslipidemias in adults, but there are fewer data on outcomes in young children. Here we examined lipid profile changes in a cohort of young children before and after suppression on an initial ritonavir-boosted lopinavir (LPV/r)-based regimen and after switch to a nevirapine (NVP)-based regimen.
Methods: One hundred ninety-five HIV-infected children who initiated LPV/r-based therapy when <24 months of age at 1 site in Johannesburg, South Africa, and who achieved viral suppression (<400 copies/mL sustained for ≥ 3 months) were randomized to either continue on the LPV/r-based regimen (n = 99) or to switch to a NVP-based regimen (n = 96). Nonfasting concentrations of total cholesterol (TC), low-density lipoprotein, high-density lipoprotein (HDL), and triglycerides (TG) were measured pretreatment, at randomization when suppressed, and at 9, 20, and 31 months postrandomization.
Results: Median age at treatment initiation was 9 months, and the initial regimen was maintained for an average of 9 months before randomization. TC, low-density lipoprotein, and HDL increased from pretreatment to randomization (P < 0.0001) and TC/HDL ratio and TG decreased (P < 0.0001). After switching to NVP, HDL was significantly higher (P < 0.02) and TC/HDL and TG significantly lower (P < 0.0001) through 31 months postswitch relative to remaining on the LPV/r-based regimen.
Conclusion: Initiating antiretroviral therapy was associated with changes to a more favorable lipid profile in young children. Switching from a LPV/r-based regimen to a NVP-based regimen accentuated and continued these improvements. Investigation of safe and effective methods for managing dyslipidemias in children of different ages in resource-limited settings is warranted.
*Empilweni Services and Research Unit, Rahima Moosa Mother and Child Hospital, University of the Witwatersrand, Johannesburg, South Africa
†ICAP, Mailman School of Public Health, and Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY
‡Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
§Harriet Shezi Clinic, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa.
Correspondence to: Louise Kuhn, PhD, Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, 630 W 168th Street, New York, NY 10032 (e-mail: firstname.lastname@example.org).
Supported in part by grants from the National Institutes of Child Health and Human Development HD 47177 and Secure the Future Foundation RES 219.
The authors have no conflicts of interest to disclose.
Received September 28, 2011
Accepted November 22, 2011
Lipid abnormalities are reported in association with HIV infection and with its treatment. Dyslipidemias occur in treatment-naive HIV-infected persons, indicating that HIV infection per se may affect fatty acid metabolism.1 Furthermore, despite clinical and virologic benefits of antiretroviral therapy (ART), therapy itself is associated with metabolic derangements, including dyslipidemias.2 ART-related dyslipidemias, even in children, are characterized by elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and plasma triglyceride (TG) levels and lower high-density lipoprotein cholesterol (HDL) levels.3–10 Protease inhibitor (PI)–containing regimens, particularly those including ritonavir (RTV), have been strongly implicated as a cause of dyslipidemias, including hypercholesterolemia and hypertriglyceridemia.2 Other antiretroviral drug classes have also been implicated.11
The limited study of lipid metabolism in infants and young children is of particular concern because they are exposed to ART during developmentally critical periods and will likely have longer cumulative exposure to ART. Current HIV treatment guidelines recommend routine use of PI-based regimens for first-line treatment of young children because of exposure to nevirapine (NVP) to prevent mother-to-child HIV transmission.12 Concerns are heightened by accumulating evidence of the importance of childhood metabolic parameters in long-term development of atherosclerosis in adults13,14 and increasing recognition of the role of early exposures in shaping development of these metabolic pathways.15 Dyslipidemias have been described in 50%–70% of children receiving ART.16–20 But studies of young children and infants are limited and generally have not followed children prospectively or compared different treatment regimens.
In the context of a trial evaluating reuse of NVP for children exposed to this agent at birth when it was used as prophylaxis,21 we examined lipid profiles of HIV-infected South African children initiating PI-based ART when younger than 2 years. We assessed changes from pretreatment to the time of viral suppression and then subsequent changes when children were either continued on their primary PI-based regimen or were switched to a NVP-based regimen. The randomized design allowed us to investigate whether switching from a PI-based regimen to a NVP-based regimen would result in measurable changes in young children's lipid profiles.
We report results of serum lipoprotein and triglyceride measurements from 195 HIV-infected infants and young children enrolled in an ART strategies trial before and after they were suppressed on their primary regimen containing ritonavir-boosted lopinavir (LPV/r).21 Children initiated treatment between April 2005 and July 2007 at a single secondary-level hospital in Johannesburg, South Africa (Rahima Moosa Mother and Child Hospital). Children were referred from inpatient wards and nearby hospitals and surrounding clinics. Participants lived mainly in the urban neighbourhoods surrounding the health facility and came from poorer socioeconomic backgrounds. All children were exposed to single-dose NVP prophylaxis at birth and were younger than 24 months of age when they initiated PI-based ART. Those who achieved and sustained plasma HIV-1 RNA <400 copies per milliliter for at least 3 months within the first 12 months of treatment were eligible for randomization to either continue on the LPV/r-based regimen or to switch to a NVP-based regimen. Here we describe the lipid profiles of the children before starting any therapy, at the time of randomization when suppressed, and at 9, 20, and 31 months postrandomization. The study was approved by the Institutional Review Boards of Columbia University (New York, NY) and the University of the Witwatersrand (Johannesburg, South Africa). Signed informed consent was obtained from the child's parent or guardian.
As per South African Department of Health guidelines in place at the time,22 children >6 months were started on LPV/r–230mg/m², lamivudine–4mg/kg, and stavudine–1mg/kg (d4T) taken 12 hourly. In children <6 months of age or those receiving concomitant rifampicin-based tuberculosis (TB) treatment, LPV/r was replaced with RTV–450mg/m². Once older than 6 months and at the completion of TB treatment, RTV was replaced with LPV/r. All children were receiving a LPV/r-based regimen at the time of randomization. Dosages were recalculated monthly according to weight. All medications were in liquid formulation.
Randomization divided the cohort into 2 groups. The control group underwent no regimen change and continued with the LPV/r-containing regimen. The switch group substituted NVP for LPV/r. Both groups continued d4T and lamivudine. If children in either group were diagnosed with TB postrandomization, they commenced antituberculous therapy, and their regimen was modified according to South African guidelines. For the switch group, this entailed discontinuation of NVP. In the event of viral failure that did not respond to adherence counseling, children in the switch group were returned to the LPV/r-based regimen. None of the children received any lipid-lowering agents.
TC, LDL, HDL, and TG concentrations were measured at 5 time points as follows: pretreatment (Time 0), randomization (Time 0R), and 9, 20, and 31 months postrandomization. Due to the young age of the cohort, children were not fasted before the blood draw. One child in each group was still breastfeeding at the time of enrollment into the study. Due to enrollment procedures, pretreatment blood samples were only available for 151 of 195 children who had been randomized. Quantitative determination of the serum lipogram was performed using the Roche COBAS INTEGRA 400 system. Lipogram values were all reported in millimole per liter. For ease of interpretation, we present key findings also in milligram per deciliter. For these calculations, we multiplied lipid values by 39 and triglyceride values by 89. Hypercholesterolemia was defined as TC ≥5.13 mmoL/L (≥200 mg/dL). LDL was classified as borderline high if between 2.82 and 3.31 mmoL/L (110–129 mg/dL) and high if ≥3.31 (≥130 mg/dL). HDL was considered low if <1.03 mmol/l (<40 mg/dL). Hypertriglyceridemia was defined as TG ≥1.69 mmoL/L (≥150 mg/dL).23 The ratio of TC to HDL was also calculated.
CD4 T-cell counts and percentages were measured pretreatment and every 3 months during follow-up. For this analysis, we selected the CD4 determinations done pretreatment, closest to the time of randomization and closest to the follow-up lipogram measurements. CD4 cell counts and percentages were obtained using the Beckman Coulter FlowCARE PLG CD4 Reagent system. HIV-1 RNA quantity (viral load) was measured pretreatment and 3 monthly until randomization, and at 1, 4, 6 months postrandomization and every 3 months thereafter. The standard assay was used for the sample collected pretreatment (quantification range 400–750 000 copies/mL) and the ultrasensitive assay (quantification range 50–150 000 copies/mL) for samples collected after ART initiation (Roche Amplicor Assay, version 1.5, Branchburg, NJ).
Clinical evaluations were performed at regular intervals and included anthropometric measurements (height, weight, and head circumference), consultation with study physicians, phlebotomy, adherence assessments, including 1-day and 2-day recall and reconciliation of returned medications and dispensing of medications.
Paired t tests were used to compare lipid values before and after treatment initiation, and McNemar tests to compare changes when classifying lipid abnormalities in categories. Treatment groups were compared as randomized (intent-to-treat). Wilcoxon rank-sum tests were used to compare continuous variables between groups and χ2 or Fisher exact tests for categorical variables. Kaplan–Meier methods were used to describe virologic endpoints. Associations on the continuous scale were examined using Spearman rank order correlations or using χ2 tests if categorical. Weight-for-age Z scores and height-for-age Z scores were calculated using WHO software.24 All P values are 2-tailed and P values <0.05 were considered statistically significant. Data analysis was performed using SAS software (Cary, NC).
The median age when treatment was started was 10 months (range: 2–24 months) in the whole cohort of 195 HIV-infected children who achieved viral suppression and were randomized, and 47% were female. Before starting therapy, 55% had HIV RNA quantity >750,000 copies per milliliter, the median CD4 percentage was 18.5, and the mean weight-for age Z score was −2.18. The characteristics of the 151 children with pretreatment samples available for lipid measurements are shown in Table 1. Those missing pretreatment samples did not differ significantly from those with available samples in age, sex, CD4 percentage, or weight-for-age. Pretreatment viral load results were missing for most of those missing pretreatment samples. In those with pretreatment samples, the median age at treatment initiation was 9.3 months, and by the time of randomization, after a mean 9.4 months on PI-based ART, all children had viremia <400 copies per milliliter (by definition), 70.9% were suppressed <50 copies per milliliter, the median CD4 percentage had risen to 29.8, and the mean weight-for-age Z score was −0.54.
Changes in Lipids With Treatment Initiation
There were significant increases in TC, LDL, and HDL and significant decreases in TC to HDL ratio and TG from pretreatment to the time of randomization when viral suppression was attained (P < 0.0001) (Table 2). Before starting therapy, TC, LDL, and HDL were low, with no children with high levels of TC or LDL, and 93.1% of children with HDL values considered low. TG above the threshold considered high were observed in 63.3% of children (Table 2). On average 9 months later, after viral suppression had been attained, TC increased by an average of 1.09 mmoL/L and LDL by 0.86 mmoL/L, and 5.6% and 7.0% of children were classified as having high TC and LDL measurements, respectively. Although HDL increased on average 0.44 mmoL/L, by the time of suppression, 59.6% were still considered to have low HDL. TG decreased 0.39 mmoL/L with 37.7% remaining elevated at randomization. Only results for the 151 children who had samples available pretreatment are shown. Those missing pretreatment samples had similar posttreatment levels to those with both time points (data not shown).
There were no significant differences by gender. Lipid changes observed with treatment occurred in both girls and boys. HDL was lower and LDL higher among children older at the time of treatment initiation but, at the time of suppression, no age associations were observed. As a result, the magnitude of the LDL increase was larger and the change in HDL smaller in children who initiated therapy younger than a year of age. Higher pretreatment HDL was associated with higher CD4 percentage. Lower LDL and higher TG were associated with higher pretreatment viral loads. There were no associations at the time of randomization.
Postrandomization Changes in Lipids
Postrandomization, lipid changes in both groups displayed similar trends to that observed after treatment initiation, namely increases in TC, LDL, and HDL and decreases in TC to HDL ratio and TG. However, increases in HDL and decreases in TG were greater in the switch group (Fig. 1). The switch group had significantly higher HDL compared with the control group at 9, 20, and 31 months postrandomization (Table 3). The switch group had continued increases in HDL after randomization with slower increases in the control group. By 31 months postrandomization, 19.0% of children in the switch group and 40.3% of children in control group had persistently low HDL (P = 0.01) (Table 4). The switch group also had more pronounced declines in TG and in TC:HDL ratio (Table 3). By 31 months postrandomization, 10.5% of children in the switch group and 35.3% of children in control group had persistently high TG (P = 0.001) (Table 4). There were no consistent differences between the groups in LDL or TC levels postrandomization. At the time of randomization, there were no significant differences between the groups in HDL, LDL, TC, or TC:HDL ratio. There was a borderline difference in TG levels, but the later larger differences between the groups remained significant after adjusting for TG levels at the time of randomization.
There were no significant differences in lipid concentrations by sex within treatment groups at any time point. However, differences between the groups in HDL were more marked among boys, and TG declines were stronger among girls. There were no consistent associations between age at starting therapy or at randomization and lipid concentrations.
As we have previously reported, children randomized to the switch group were significantly more likely to meet the virological endpoint used in the trial to consider regimen change (defined as confirmed viremia >1000 copies/mL) than children randomized to the LPV/r group. By 9 months, 17.2% of children in switch group had confirmed viremia >1000 copies per milliliter compared with 2.2% in the control group. By 20 and 31 months, respectively, these proportions were 23.9% and 23.9% in the switch group; and 9.6% and 11.1% in the control group (P = 0.009). There were no significant differences in lipids in those who failed virologically overall or within treatment group, but numbers of failures were small. The associations between group assignment and HDL, TC:HDL ratio and TG persisted if the analysis was restricted only to those who did not fail therapy.
In this randomized clinical trial, young HIV-infected children had low TC, HDL and LDL, and high plasma TG before starting therapy. Initiation of a PI-based regimen resulted in significant increases in TC, LDL, and HDL, and decreases in TC:HDL ratio and TG. This pattern corresponds with prior descriptions of viremia-associated dyslipidemia and changes after therapy.4,25 However, even when virologically suppressed, a large proportion of children still had low HDL and high TG. After randomization, only those switched from their LPV/r-based regimen to the NVP-based regimen showed further significant improvements in HDL, TC:HDL ratio, and TG levels.
Although metabolic abnormalities have been well described among HIV-infected children and youth on treatment,2–9,16,20,25 fewer studies have characterized patterns of dyslipidemia among young children before ART. Among untreated adults, there is an early decrease in HDL followed by decreases in LDL and increases in TG.26 Chantry et al18 reported that, in a cohort of ART-naive children, 30% had HDL abnormalities compared with 4% among a matched comparison group. Among 103 ART-naive children in London with mild/moderate HIV disease, median age 7.1 years, lipid levels were normal with the exception of below normal HDL.20 In the British cohort, no association was found between lipids and viral load or CD4+ cell count.20 In our young cohort, where most children had advanced disease, 93% had low HDL and 63% had elevated TG before ART initiation. Lower LDL and higher TG were associated with higher HIV RNA although higher HDL was associated with higher CD4 percentage. The high rate of lipid abnormalities pretreatment may be related to the young age and advanced state of disease among children in our cohort. We hypothesize that the initial improvements in lipids may be secondary to ART-mediated control of viral replication and restoration of immune function.
Those children randomized to remain on the LPV/r-based regimen continued to have increases in TC, LDL, and HDL and declines in TC:HDL ratio and TG. Despite 31 months of treatment, high rates of abnormalities persisted in this group including high TC (16%), LDL (12%), TG (36%) and low HDL (40%). Among children randomized to switch to NVP-based treatment, the pattern of improvement in lipids (HDL increase and TC:HDL and TG decline) was more pronounced. In comparison to those remaining on LPV/r-based therapy, HDL was significantly higher and TC/HDL and TG significantly lower through 31 months among those switched to the NVP-based regimen.
Several studies have documented lipid abnormalities among children on treatment, but most of these studies have been observational and included older children on a variety of different ART regimens. Our study is randomized and focuses only on young children younger than 2 years when initiating ART. In a large multisite cross-sectional study in the United States, Aldrovandi et al8 found a high prevalence of lipid abnormalities among treated children compared with seronegative controls as follows: among 161 children receiving PI-based ART, 52% had elevated TG, 29% high TC, 19% high LDL, and 10% low HDL (<35 mg/dL). Each year of RTV use was associated with increases in TC, TG, and LDL although NVP and efavirenz were associated with increases in HDL.8 Among 441 children followed in London, Rhoads et al20 evaluated changes in lipid levels and associations with individual antiretroviral drugs. All lipids rose over a period of 4.5 years of observation. LPV/r was associated with increases in non-HDL of 0.43 mmoL per year in the first 0 to 1 year and 0.8 mmoL per year at >4-year exposure compared with a more modest effect of NVP with increases of 0.2–0.39 mmoL per year.
Our findings highlight the subtleties of the metabolic effects of different antiretroviral agents. It is likely that the early impact of ART initiation, which leads to correction of HIV-related dyslipidemia (even with a LPV/r-based regimen) is balanced, over time, by the specific drug-related lipid abnormalities associated with this regimen. By comparison, in the switch cohort, the additional improvements in lipid profile can be attributed to the particular characteristics of NVP, which have been associated with a more favorable lipid profile and lower long-term cardiovascular risk.27 Several substitution studies in adults where a PI was switched to NVP resulted in significant improvements in dyslipidemia changes, which are likely due to both the discontinuation of the PI and the specific drug substitution.27–30 A pediatric study also observed significant improvements in lipid profile with switch to efavirenz.31
Recent developments in ARTs offer an increasingly large array of treatment options for adults with HIV infection. Many of the newer agents have better toxicity profiles and, in well-resourced settings, drug regimens can be individualized to improve efficacy, facilitate adherence, and minimize both short-term and long-term side effects. Unfortunately, for children, particularly infants and young children, treatment options remain profoundly limited. LPV/r-based regimens are currently recommended for children who have been exposed to NVP used as part of prevent mother-to-child HIV transmission.12 The comparative virologic efficacy of different regimens is important, but other short-term and long-term impacts on other disease parameters also need to be studied to understand how to optimize use of the available drugs.
The long-term consequence of abnormal lipids in infants and young children with HIV infection is unknown. Several studies have identified early atherosclerotic changes with carotid artery imaging studies among youth with perinatal HIV infection and long-term ART exposure.32,33 With increased availability of ART in high HIV prevalence settings, increasingly large numbers of infants and young children are initiating treatment, with either NVP-based or LPV/r-based regimens. The long-term consequences of ART starting early in life and extending through childhood and adolescence are unknown but warrant careful study. Childhood metabolic parameters are associated with atherosclerosis and cardiovascular disease in adulthood. Current guidelines in the United States recommend biannual monitoring of fasting lipids in children on ART, but such tests are generally not available in resource-constrained settings.34 Recommendations for management of lipid abnormalities include switching antiretroviral drugs, exercise and dietary interventions, and, for older children, use of lipid-lowering agents but are not widely implemented.19,34 Most commercially available lipid-lowering medications have not been studied in children with HIV.
There are several limitations of our study. Due to the young age of the cohort, fasting blood samples were not obtained. Although most normative lipoprotein reference data are based on fasting samples, sample timing with respect to feedings does not significantly influence results.35 Our approach is also similar to many of the published pediatric studies, and our findings seem comparable. Moreover, because the same protocols were followed for the collection of samples pretreatment and post-treatment and between the groups, any measurement error introduced is likely to be nondifferential resulting in weaker associations. We note that our reference levels are based on data obtained from children in North America as there are no population-specific lipid reference levels for South African children. No information on the children's diet or family history of lipid disorders was recorded, but because the study is randomized, this is unlikely to have any consequence. Because all children received d4T, the individual impact of this agent could not be discerned.36
We have previously reported on the virologic constraints of reusing NVP in NVP-exposed children and on the benefits of switching for CD4 response and growth.21 These new results demonstrate the potential value of switching from an initial LPV/r-based regimen to a NVP-based regimen in young HIV-infected children on select metabolic parameters. Those children who were switched had a more favorable lipid profile with higher HDL and lower TC:HDL ratio and TG concentrations. Although the long-term clinical implications of these changes are unknown, our results raise concern about the long-term risk of cardiovascular disease with prolonged use of LPV/r-based therapy initiated in infants and young children. Our study reinforces the need for ongoing monitoring of the lipid profile of treated children, especially those receiving boosted PI. Investigations of safe and effective methods for managing dyslipidemias in children of different ages in resource-limited settings are warranted.
We thank the study participants and caregivers and the clinical and administrative team for their continued dedication and support.
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