To our knowledge, this is the first study to investigate the association between lopinavir concentrations and serum glucose concentrations, and the first to investigate associations between lopinavir concentrations and serum lipids in a South African population. Despite a high prevalence of dyslipidaemia (29%) and dysglycaemia (42%) in 84 black South African HIV-infected adults treated with ritonavir-boosted lopinavir for a median duration of 19 months, we found no association between plasma lopinavir concentrations and lipid or glucose concentrations. There was also no significant association between the lopinavir concentrations above the median, and hypercholesterolaemia, hypertriglyceridaemia or dysglycaemia.
We found the median lopinavir concentration was 8 μg/mL, which is higher than reported elsewhere [17, 18], but comparable to the trough concentrations after observed doses in a study conducted by our group from the same community . Lopinavir pharmacokinetics demonstrate considerable interindividual variability, which may affect treatment outcomes. At least part of this variability may be explained by host genetic factors. Associations between human genetic variants and lopinavir exposure are incompletely understood and need to be explored.
The lack of an association between lopinavir concentrations and lipid or glucose concentrations that we found can be explained as follows: First, like all protease inhibitors, lopinavir exerts its antiviral activity intracellularly, and the plasma and intracellular half-lives are different . However, the positive correlation between lopinavir plasma and intracellular concentrations reported at 4 weeks was not sustained at 24 weeks of treatment . More importantly, the mechanism of toxicity associated with protease inhibitor use, including lopinavir, is still poorly understood, but is thought to be related to interference with some cellular endogenous processes. For example, lopinavir binds to lipoprotein receptor related protein (LPR), impairing hepatic chylomicron uptake and triglyceride clearance by LPR –lipoprotein lipase complex, causing hyperlipidaemia . In susceptible individuals, the resulting hyperlipidaemia may induce diabetes . Second, clinical manifestations of LPV/r toxicity are also influenced by host susceptibility such as age, sex, weight, race, advanced HIV disease, concomitant ART, higher baseline triglyceride or cholesterol concentrations, and genetic susceptibility [2, 22, 23]. Finally, we hypothesize that the if the association between plasma lopinavir concentrations and toxicity exists, it exists in much lower concentrations, as the dose–response curve is likely to be flat at the concentrations found in our study. Therefore, the influence of lopinavir plasma concentrations on lipids at therapeutic doses, is likely to be small and larger studies are needed to detect the small differences. Furthermore, recent data suggests that lopinavir does not impair insulin sensitivity [7, 8], and therefore, the lack of an association between lopinavir and glucose concentrations is not surprising.
Our findings are in contrast with findings from a small study conducted in 19 patients, which reported that lopinavir trough concentrations were higher in three patients experiencing grade 3 or 4 lipid elevations . A second larger study (n=126) found that patients with fasting triglyceride concentrations above the median had higher lopinavir trough concentrations, but no correlation was found between lopinavir and cholesterol concentrations . Four other studies reported findings similar to ours, with no association between lopinavir and lipid concentrations [12, 17, 24, 25]. The older protease inhibitor indinavir is known to cause diabetes . However, after 12 months of treatment with lopinavir, none of the 73 patients included in another study developed diabetes . Studies in healthy volunteers have shown that insulin sensitivity wasn’t altered by lopinavir in healthy HIV negative men [7, 8]. However, a single dose study in healthy volunteers showed that lopinavir could inhibit glucose uptake acutely . Data regarding the association between lopinavir concentrations and glucose metabolism are lacking.
Our study has several limitations. First, it is a cross sectional study and we therefore cannot compare lipid or glucose concentrations prior to lopinavir treatment. Second, patients with known diabetes or dyslipidaemia were excluded from the study, and it is possible that lopinavir may have exacerbated a pre-existing metabolic defect. Third, our sample size is relatively small, however, it is larger than most of the previous studies that have investigated this association [11, 17, 19]. We aimed to examine 50 participants to detect a correlation of 0.375. Our analyses used simple and multivariate regression analyses with various predictors, therefore we continued to slowly recruit eligible participants until the end of the study. Fourth, we investigated associations with pre-dose lopinavir concentrations and metabolic parameters. The pharmacokinetic parameters area under the curve or average steady state would be a better measure of overall drug exposure. Lastly, the last dose of lopinavir was not observed. To minimize recall bias, participants were requested to record the time of last dose on the appointment card for the day before pharmacokinetic sampling.
In conclusion, we did not find an association between lopinavir concentrations and lipid and glucose concentrations. Larger prospective studies are needed to establish whether an association exists between lopinavir concentrations and increasing lipids or glucose metabolism changes.