July 10, 2001
This substudy of the large multi-center, randomized COMBINE trial looked at body composition and metabolic changes in patients on combivir plus nelfinavir (CNf) compared to those on combivir plus nevirapine (CNr).
It involved 43 patients (CNf, n=20; CNr, n=23), who were followed for up to 12 months. Body composition was measured by bioelectric impedance analysis (BIA) and standard anthropometrics. Lipodystrophy was assessed by clinical examination and abdominal computed tomography. Fasting total cholesterol (TC), high and low density lipoprotein cholesterol (HDLc and LDLc), triglycerides (TG), glucose, insulin, insulin resistance by HOMA (homeostasis model assessment) and C-peptide levels were also determined.
At baseline there were no differences in anthropometrics or metabolic findings. At follow-up there was a significant elevation of the total (<0.05) and HDL cholesterol (CNf, p<0.05; CNr, p<0.01) in both treatment arms. Levels of LDLc increased significantly in the nelfinavir arm (p<0.05), from 3.11 to 3.64 mmol/L and remained stable in the nevirapine patients. The prevalence of patients with LDLc levels >4.13 mmol/L increased to 31.2% in the CNf group from a baseline of 12.5% and decreased by half in the CNr group, from 12.5% to 6.2%. In the CNf group a 1.41 fold non-significant TG increase (from 1.52 to 2.15 mmol/L) was noted, whereas in the CNr group TG mean values remained unchanged. When both treatments were compared at follow-up (as above up to 12 months), significant differences (p<0.05) in HDLc (1.28 vs. 1.57 mmol/L) and HDLc:TC ratio (0.24 vs. 0.31) occurred.
This study is an important confirmation of the fact that protease inhibitors -- in this case nelfinavir -- are associated with lipid abnormalities, whereas nevirapine is not. This study used multiple and appropriately quantifiable measurements of all parameters. Unlike many other studies done to date, especially those from Europe, this one is not complicated by the concurrent use of a d4T-containing regimen (although the role of ZDV in causing lipodystrophy is still not totally clear). It is also interesting to note that this study used nelfinavir as the protease inhibitor. Nelfinavir is generally considered to cause less lipid abnormalities than some of the other protease inhibitors. It would be interesting to see what the results would have looked like with a ritonavir-boosted regimen, for example. One may assume that the differences would have been even more striking.
|Biochemical Characteristics at Baseline and at Follow-Up|
|Glucose (mmol/L)||4.95 + 0.41||5.22 + 0.53||4.89 + 0.56||4.81 + 0.55|
|Insulin (pmol/L)||90.1 + 46.4||121.1 + 80.0||109.9 + 61.1||106.4 + 58.2|
|C-Peptide (mmol/L)||0.99 + 0.32||0.94 + 0.32||0.94 + 0.28||0.94 + 0.28|
|Insulin Resistance HOMA||2.93 + 1.60||4.01 + 2.62||3.49 + 2.25||3.28 + 2.00|
|Total cholesterol (mmol/L)||4.79 + 1.05||5.62 + 1.55||0.005||4.72 + 0.96||5.20 + 0.82||0.04|
|HDLc (mmol/L)||1.07 + 0.31||1.28 + 0.35||0.001||1.09 + 0.27||1.57 + 0.38||<0.01|
|LDLc (mmol/L)||3.11 + 0.82||3.64 + 1.08||0.031||2.99 + 0.93||2.91 + 0.69|
|HDLc: TC Ratio||0.22 + 0.05||0.24 + 0.07||0.24 + 0.07||0.31 + 0.07||<0.01|
|Triglycerides (mmol/L)||1.52 + 0.74||2.14 + 2.04||1.72 + 1.16||1.69 + 1.63|
|*Baseline vs. follow-up within groups|
|Percentages of Patients Above (or Below, for HDLc) Desirable Lipid Levels|
|Total Cholesterol >6.2 (mmol/L)||6.2%||37.5%||5.6%||11.1%|
|LDLc >4.13 (mmol/L)||12.5%||31.2%||12.5%||6.2%|
|HDLc <0.9 (mmol/L)||31.2 %||12.5%||11.8%||5.6%|
|TG >2.3 (mmol/L)||12.5%||25%||17.6%||16.7%|
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