9 research outputs found
Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study
Abstract
Background
Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids.
Aim
To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV-infected South African adults.
Methods
Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations.
Results
There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) ΞΌg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (Ξ²-coefficient β0.04 (95% CI β0.07 to 0.00)), triglycerides (Ξ²-coefficient β0.01 (95% CI β0.04 to 0.02)), fasting glucose (Ξ²-coefficient β0.01 (95% CI β0.04 to 0.02)), or 2-hour glucose concentrations (Ξ²-coefficient β0.02 (95% CI β0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia.
Conclusions
There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations
Lack of association between stavudine exposure and lipoatrophy, dysglycaemia, hyperlactataemia and hypertriglyceridaemia: a prospective cross sectional study
<p>Abstract</p> <p>Background</p> <p>Stavudine continues to be widely used in resource poor settings despite its toxicity. Our objective was to determine association between plasma stavudine concentrations and lipoatrophy, concentrations of glucose, lactate and triglycerides.</p> <p>Methods</p> <p>Participants were enrolled in a cross-sectional study with lipoatrophy assessment, oral glucose tolerance test, fasting triglycerides, finger prick lactate, and stavudine concentrations. Individual predictions of the area under the concentration curve (AUC) were obtained using a population pharmacokinetic approach. Logistic regression models were fitted to assess the association between stavudine geometric mean ratio > 1 and impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, hypertriglyceridaemia, and lipoatrophy.</p> <p>Results</p> <p>There were 47 study participants with a median age of 34 years and 83% were women. The median body mass index and waist:hip ratio was 24.5 kg/m<sup>2 </sup>and 0.85 respectively. The median duration on stavudine treatment was 14.5 months. The prevalence of lipoatrophy, impaired fasting glucose, impaired glucose tolerance, hyperlactataemia, and hypertriglyceridaemia were 34%, 19%, 4%, 32%, and 23% respectively. Estimated median (interquartile range) stavudine AUC was 2191 (1957 to 2712) ng*h/mL. Twenty two participants had stavudine geometric mean ratio >1. Univariate logistic regression analysis showed no association between stavudine geometric mean ratio >1 and impaired fasting glucose (odds ratio (OR) 2.00, 95% CI 0.44 to 9.19), impaired glucose tolerance (OR 1.14, 95% CI 0.07 to 19.42), hyperlactataemia (OR 2.19, 95%CI 0.63 to 7.66), hypertriglyceridaemia (OR 1.75, 95%CI 0.44 to 7.04), and lipoatrophy (OR 0.83, 95% CI 0.25 to 2.79).</p> <p>Conclusions</p> <p>There was a high prevalence of metabolic complications of stavudine, but these were not associated with plasma stavudine concentrations. Until there is universal access to safer antiretroviral drugs, there is a need for further studies examining the pathogenesis of stavudine-associated toxicities.</p
Pharmacogenomics and pharmacokinetics of antiretroviral drugs and their associations with metabolic complications in HIV-infected Black South Africans
BACKGROUND: Antiretroviral therapy (ART), notably efavirenz and lopinavir, have been associated with metabolic abnormalities known to increase cardiovascular risk. Efavirenz and lopinavir pharmacokinetics demonstrate considerable interindividual variability, which in part, may be explained by host genetic factors. Mitochondrial DNA (mtDNA) variation influences ART related metabolic complications. However, the associations between genetic polymorphisms and pharmacokinetics of antiretroviral drugs, and their associations with metabolic complications, are incompletely understood. We explored associations of mitochondrial DNA (mtDNA) haplogroups and ART related metabolic complications, characterized relationships between genetic polymorphisms and plasma efavirenz concentrations, and investigated associations between plasma efavirenz/lopinavir concentrations and lipid and glucose concentrations in HIVinfected Black South Africans. METHODS: We collected clinical and laboratory data from HIV infected patients on ART from Cape Town. We sequenced the mitochondrial genome and determined African mtDNA haplogroups. We genotyped 241 polymorphisms in genes potentially relevant to efavirenz metabolism and transport. We measured steady state efavirenz and lopinavir concentrations and used regression analyses to determine associations with metabolic parameters
Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.
Background:There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz. Objectives:We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance. Methods:We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold. Results:We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (Ξ²β=β0.38, Pβ=β2.7βΓβ10-03), plasma 7-hydroxy-efavirenz (Ξ²β=β0.59, Pβ=β3.7βΓβ10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (Ξ²β=β-0.31, Pβ=β1.8βΓβ10-04) and CSF efavirenz (Ξ²β=β0.36, Pβ=β0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (Ξ²β=β-0.55, Pβ=β3.5βΓβ10-05), ABCB1 rs115780656 (Ξ²β=β-0.65, Pβ=β4.1βΓβ10-05) and CYP2A6β-48AβC (Ξ²β=β-0.59, Pβ=β0.01). CYP2A6β-48AβC was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (Ξ²β=β0.54, Pβ=β0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (Pβ<β0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance. Conclusions:We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio