The high prevalence10
and incidence of hypercholesterolemia20
previously reported in this cohort of perinatally HIV-infected children and in other studies of children 9–14
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 current analysis, the majority of children with incident hypercholesterolemia failed to demonstrate resolution of elevated cholesterol levels over two 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. While 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 protease inhibitors,10, 13, 15–19
especially ritonavir10, 12, 18
and some NRTIs in HIV-infected children. Previous work in this cohort also found that children on PIs, boosted or non-boosted with ritonavir, were more likely to develop hypercholesterolemia20
. 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, while few were done in children21–28, 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. While 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 one change in their ARV regimen over two years, but 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 decrease22, 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 non-adherence. 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 and older were more likely to revert to normal cholesterol. This may be partially explained by data from NHANES which showed that mean cholesterol levels peak at ages 9–11 and then decline in older children34
. Children over 13 years old 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 cohort35
. Poorer adherence could reduce exposure to deleterious effects of specific ARV, including hypercholesterolemia as shown by Tassiopoulos et al. in the examination of risk factors for developing hypercholesterolemia in the 219C cohort20
HIV-infected adults with dyslipidemia have benefited from statin use30, 31
. Clinical trials of statins in infected children began after 219C was complete. This may explain why 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 current 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, few studies have addressed management of children with hypercholesterolemia. We characterized clinical management of these children with available data, 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.