Prospective Study of Glucose and Lipid Metabolism in Antiretroviral-Naive Subjects Randomized to Receive Nelfinavir, Efavirenz, or Both Combined with Zidovudine+Lamivudine (ZDV+3TC) or Didanosine+Stavudine: A5005s, a Substudy of ACTG 384
M Dubé*1, R Zackin2,3, R Parker2,3, Y Yang2,3, S Grinspoon3, P Tebas4, G Robbins3, R Shafer5, S Snyder6, K Mulligan7, and Adult AIDS Clinical Trials Group
1Indiana Univ, Indianapolis, IN, USA; 2Statistical and Data Analysis Ctr., Boston, MA, USA; 3Harvard Univ., Boston, MA, USA; 4Washington Univ., St. Louis, MO, USA; 5Stanford Univ., Palo Alto, CA, USA; 6ACTG Operations Ctr., Silver Spring, MD, USA; and 7Univ. of California, San Francisco, USA
Background: The primary objective of A5005s was to
determine whether nelfinavir (NFV)- and efavirenz (EFV)-based therapies differ
with respect to changes in fasting lipids and insulin resistance. Secondary
objectives included comparisons among NRTI regimens.
Methods: Antiretroviral-naive subjects (n = 334) received NFV (99), EFV (110),
or both (125) plus zidovudine (ZDV) + lamivudine (3TC) (154) or didanosine (ddI)
+ stavudine (d4T) (180) in a substudy of a 3x2 randomized factorial trial.
Fasting samples were collected at entry, 8, 16, 32, 48, and 64 weeks. Primary
analyses (Wilcoxon tests) are intent-to-treat; changes from entry are reported
as median [IQR] at week 32. The EFV+NFV group was excluded from NFV vs EFV
comparisons, but included in NRTI analyses.
Results: Lipid values (mg/dL) increased in all groups.
The proportion with total-C >200 increased from 13% to 45% at week 32; those
with HDL-C <40 fell from 75% to
48% (each p <0.001). HDL-C increases correlated with higher HIV RNA and
lower CD4 at entry (each p <0.001).
Similar increases occurred with both NFV and EFV in total-C (NFV 28 [9, 56],
EFV 25 [9, 52], non-HDL-C (22 [7, 52]
versus 19 [0, 42]), and triglycerides (TG) (13 [-13, 56] versus 32 [-19, 76]).
Only 6% with EFV and 5% with NFV had TG >400 at week 32. HDL-C
increases tended to be greater with EFV (7 [2, 12]) than NFV (5 [0, 10], p = 0.11), with a more favorable change
in total:HDL-C ratio with EFV
(-0.4 versus 0.4, p = 0.03). There
was some evidence of greater increases in total-C with ddI+d4T (45 [12, 71]) versus
ZDV+3TC (29 [10, 55], p = 0.07) and
non-HDL-C (35 [10, 60] versus 26
[0, 52], p = 0.12). HDL-C (8 [2, 14] versus 7 [0, 12]) and TG (30 [-13,
84] versus 25 [-14, 60]) increases were similar. Insulin resistance (by
increased over time for the whole group. From a baseline of 1.39 [0.90, 2.05],
median change at week 8 was 0.20 [-0.37, 0.72] (p = 0.03); no
changes were significant within any group. At week 32, the overall
median increase was 0.38 [-0.22,0.97] (p
= 0.002), but differences in the change in HOMA-insulin resistance between
groups were minimal: NFV 0.41 [-0.37, 1.43],
EFV 0.39 [-0.17, 0.82] (p = 0.9);
ddI+d4T 0.32 [-0.29, 0.85], ZDV+3TC 0.40 [-0.19, 1.30] (p = 0.4).
the PI NFV and the NNRTI EFV appear to have comparable effects on fasting
lipids, with a better total:HDL-C
ratio with EFV. Lipids tended to be slightly more favorable with ZDV+3TC than
ddI+d4T. HDL-C changes correlated
with entry HIV disease status. Insulin
resistance worsened in the group as a whole, but did not differ between
regimens. The lack of an early increase in insulin resistance with NFV suggests that acute insulin
resistance is not a PI drug class effect.
Keywords: lipids; insulin resistance; protease inhibitors