The Body Covers: The 8th European Conference on Clinical Aspects and Treatment of HIV-Infection
October 30, 2001
In contrast, ritonavir had a marked, dose-dependent effect on the GLUT4 transporter, consistent with previous work on indinavir and amprenavir. In liver cells (the cultures used a type of liver tumor cell called HepG2), atazanavir also had no effect on the output of cholesterol or triglycerides from these cells, whereas ritonavir, and to a lesser extent nelfinavir, caused increased cholesterol synthesis. Increased output of triglycerides and cholesterol from the liver has been demonstrated in healthy volunteers given ritonavir, so these cultures may reflect the clinical picture. These data are all very encouraging for atazanavir. This agent also has the advantage of being a once-daily, low-tablet volume (two per day) protease inhibitor. However, comparative data on efficacy, tolerability and lipid disturbances are all required from clinical studies before this agent can move into clinical practice.
Previously reported data have shown atazanavir to have safety and efficacy similar to that of nelfinavir (NFV) when combined with d4T and ddI in treatment-naive HIV-positive subjects. A second study confirmed these data on the backbone of d4T+3TC during the ECCAT conference.
The safety elements of this study included fasting lipid assessments. Patients from Europe, North and South America, Thailand and South Africa were all included in the analysis. Examination of changes in total cholesterol (TC), HDL cholesterol (HDL), LDL cholesterol (LDL), and triglycerides (TGs) from baseline to 48 weeks for two dose levels of atazanavir (400mg (n=181) and 600mg (n=195) OD) versus changes with NFV (1,250mg BD (n=91)) each combined with d4T and 3TC in treatment-naive subjects was reported. Inclusion criteria for the study were HIV RNA >2,000 cps/mL and CD4 >100 cells/mm3 or >75 if there was no AIDS-defining diagnosis. All patients were evaluated in the study for the lipid endpoints.
Baseline demographics were similar across all arms with 45% non-Caucasian and 37% women. The median viral load was 4.74 log and CD4 273 cells/mm3. Efficacy (as assessed by the proportion of participants with a viral load <50 cps/ml by intent to treat) and adverse event rates were similar across study arms. TC, LDL, and TG levels for both doses of atazanavir were minimally elevated from baseline relative to TC, LDL, and TG elevations from baseline in the nelfinavir arm (P<0.0001). These increases with NFV were established by week 16 and persisted through week 48. Increases in HDL were equivalent across study arms. Mean percent change in lipids for atazanavir 400, atazanavir 600 and nelfinavir arms at week 48 were respectively: Cholesterol 5%, 6% and 25%; LDL ("bad") cholesterol 5%, 7%, 23%; and triglycerides 7%, 8% 50%. In all cases differences between TAZ and nelfinavir arms were statistically significant.
These data indicate that atazanavir does not elevate TC, LDL, and TG concentrations in treatment-naive subjects, as is commonly seen with currently approved protease inhibitors. This advantage suggests that atazanavir does not lead to dyslipidemia and may be associated with a relative reduction in the risk of future cardiovascular events.
October 30, 2001
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