Objective: Simplification of antiretroviral regimen in human immunodeficiency virus (HIV)-infected children has not yet been investigated. In general, children have a more difficult time maintaining viral suppression because of many factors, including frequent nonadherence and less availability of antiretrovirals in palatable forms. In addition, many serious metabolic complications have emerged in HIV-infected adults and are believed to be attributable to antiretroviral therapy. Some of these complications--hypercholesterolemia, hypertriglyceridemia, and insulin resistance--are believed to be the result of the use of protease inhibitor (PI) therapy, whereas the cause of others, such as lipodystrophy, remains undetermined. Recent reports underline that children experience long-term metabolic abnormalities in the same manner that adults do, and perhaps these consequences are even more worrisome in children secondary to long-term expected survival. We report here the results of the first open-label PI-switch study in HIV-infected children.
Methods: Seventeen children, 24 to 160 months of age (median: 120), were enrolled into the study. All were receiving a stable PI-containing antiretroviral regimen that containing 2 to 3 nucleoside analogue reverse transcriptase inhibitors (NRTIs) in addition to 1 to 2 PIs for a median duration of 21 months (range: 5-50) before study entry. All children had HIV-1 RNA <400 copies/mL at screening; their baseline plasma HIV-1 RNA level had been <400 copies/mL for a median of 13 months (range: 4-55) before study entry. All patients were naïve to nonnucleoside reverse transcriptase inhibitor therapy. Their protease inhibitor(s) was switched to efavirenz while their NRTI therapy was maintained.
Results: All children were heavily pretreated; 88% of the patients had previous NRTIs, and 41% had previous PI use. The most common PI at study entry was nelfinavir (47%), followed by ritonavir (29%), then amprenavir (18%); only 1 was on saquinavir/ritonavir. At study entry, the duration of previous antiretroviral therapy was between 21 and 123 months (median: 88). All patients completed the 48-week study. No acquired immunodeficiency syndrome-defining events occurred. There were no rashes and no changes in liver transaminases. Mild, transient insomnia and dizziness each occurred in 1 child. Two other subjects (6 and 8 years old) experienced unusual vivid dreams, mostly pleasant, which decreased in intensity and frequency after the first 12 weeks of the study. One subject, a 10-year-old girl, had an episode of generalized seizure at week 6; study drugs were not interrupted, and seizure never recurred. The patient had a strong family history of epilepsy, although she had never experienced previous seizures. No anticonvulsants were given. Sixteen of 17 patients had HIV-1 RNA levels of <50 copies/mL (1 HIV-1 RNA was 61 copies/mL) at week 48. The mean CD4% remained stable initially from a mean of 35.1% (+/-2.8%) at baseline to 36.8% (+/-5%) at week 24, but increased to 38% (+/-6%) at week 48. Fasting triglycerides decreased from a mean of 126 mg/dL (+/-50) at baseline to 86 mg/dL (+/-45) at week 24 and to 94 mg/dL (+/-38) at week 48. At study entry, 12 (71%) of 17 children had triglyceride levels greater than the 95th percentile for age, race, and gender, compared with only 6 (35%) of 17 at week 48. Fasting cholesterol levels decreased from a mean of 203 mg/dL (+/-50) at baseline to 173 mg/dL (+/-31) at week 24 and to 174 mg/dL (+/-27) at week 48. At study entry, 5 (29%) of 17 children had cholesterol levels greater than the 95th percentile for age, race, and gender, compared with only 1 (6%) of 17 at week 48. The decrease in low-density lipoprotein cholesterol was also significant, from a mean baseline of 124 mg/dL (+/-42) to 100 mg/dL (+/-28) at week 24 and to 105 mg/dL (+/-20) at week 48. High-density lipoprotein (HDL) cholesterol did not change significantly, but the changes in cholesterol:HDL ratio, a better marker of atherogenic risk, significantly decreased from a mean baseline of 3.8 (+/-0.8) to 3.2 (+/-0.7) at week 24 and to 3 (+/-0.6) at week 48. Detailed dietary history revealed no significant changes during the study. In addition, none of the patients initiated therapy with lipid-lowering agents. There were no significant changes in insulin or C-peptide throughout the study period. In addition, anthropometric measurements that included mid-thigh and mid-arm circumferences, triceps and thigh skinfolds, and waist:hip ratio were stable throughout the study period. For bioelectrical impedance measurements, lean body mass increased from a mean baseline of 32.1 lb (+/-9.3) to 35.7 lb (+/-11.4) at week 24 and to 36.5 lb (+/-11.5) at week 48. Bioelectrical impedance measurements of fat content were unchanged throughout the study period.
Conclusion: This is the first study in children to evaluate the substitution of PI in a virologically successful regimen with efavirenz, a potent once-daily nonnucleoside reverse transcriptase inhibitor therapy. We were able to show significant improvement in fasting total cholesterol, low-density lipoprotein cholesterol, triglycerides, and, more important, the cholesterol:HDL ratio. In addition, switching to an efavirenz-containing regimen was well tolerated and successfully maintained virologic suppression in all HIV-infected children in this study. This study should encourage large randomized trials to investigate simplification strategies in HIV-infected children.