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Metabolic Outcomes of ACTG 5142: A Prospective, Randomized phase III trial of NRTI-, PI-, and NNRTI-sparing Regimens for Initial treatment of HIV-1
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Here is a preliminary report from today at CROI with more detailed reports to follow.
Reported by Jules Levin
CROI, Los Angeles, Feb 26, 2007
Richard Haubrich from the ACTG presented these study results at this morning's oral session on metabolics. The 96-week results were unexpected and surprised conference attendees. Lipoatrophy was found to be more frequent in the efavirenz+ 2 nukes arm than the Kaletra+ 2 nukes arm. The study investigators reported that 32% of patients receiving efavirenz+ 2 nukes developed lipoatrophy compared to 18% of the patients receiving Kaletra+2 nukes. And 8% for patients receiving Kaletra+efavirenz without nukes.
Patients taking Kaletra had a 9.8% increase in extremity fat at week 96. Patients taking EFV had a decrease of 1.4% in extremity fat. Patients taking EFV+LPV/r had an 18% increase in extremity fat. These were the median changes from baseline. Trunk fat increased 12-16% and was not different across randomized groups. The investigators reported the odds ratio was 2.7 for EFV vs Kaletra to develop lipoatrophy, which was defined as a loss of >20% in fat (ACTG definition). While the odds ratio for fat loss for tenofovir vs AZT was 0.24, and the odd ratio for d4T vs AZT was 1.9. These values were all statistically significant.
Of note, the study examined rates of lipoatrophy based on which nuke patients were taking (all patients took 3TC). The rates of lipoatrophy did not change no matter which nuke a patient was taking; Kaletra still had lower rates of lipoatrophy compared to efavirenz.
The study also examined lipids. Serum lipids increases were greatest in the LPV/r (Kaletra)+ EFV regimen. Increases in total cholesterol and fractions were similar in LPV/r and EFV + 2 nuke regimens, but triglycerides were significantly higher with LPV/r. The median change in total cholesterol was: +57 for LPV/r+EFV, +32 for LPV/r, and +33 for EFV. For triglycerides LPV/r had greater increases: +46 for LPV/r, +19 for EFV, and +62 for LPV/r+EFV.
Lipoatrophy was most frequent in the d4T arm and least frequent in the tenofovir arm
Increases in both HDL & non-HDL cholesterol were not different between 2 NRTI+LPV/r (8 and 26 mg/dL) or EFV (9 and 22 mg/dL, p>0.3). At baseline total cholesterol was (mg/dL) was 153 for EFV regimen, 155 for LPV/r regimen, and 152 for LPV/r+EFV nuke sparing regimen. HDL at baseline was 35 for EFV, 35 for LPV/r, and 34 for LPV/r+EFV. Non-HDL was 119 for EFV, 116 for LPV/r, and 117 for LPV/r+EFV. Triglycerides were 116 for EFV, 112 for LPV/r, and 118 for EFV+LPV/r. LDL was 91 for EFV, 90 for LPV/r, and 93 for EFV+LPVr.
Of note was a second presentation described below that compared Kaletra monotherapy to efavirenz and found no lipoatrophy. Here is the abstract from the conference program:
Background: The metabolic effects of lopinavire (LPV)- or efavirenz (EFV) -based regimens + 2 nucleoside reverse transcriptase inhibitors (NRTI) have not been compared nor has the role of an NRTI-sparing regimen in preventing lipoatrophy been tested.
Methods: This open-label, randomized trial compared class-sparing regimens for naive subjects: LPV+EFV vs LPV+2 NRTI (LPV soft-gel twice daily) vs EFV+2 NRTI. NRTI were selected before randomization from zidovudine (ZDV), stavudine (d4T XR), or tenofovir (TDF) (each plus lamivudine [3TC]). Metabolic objectives included evaluation of changes in fat (DEXA) and fasting lipids. DEXA and lipids were performed at baseline, and 48 and 96 weeks. Lipoatrophy was defined as ≥20% loss of limb fat from baseline. All analyses were intent to treat without adjustment for multiple comparisons or regimen changes. Pairwise comparisons used non-parametric tests.
Results: We enrolled 753 subjects (median CD4 182 cells/mm3, median HIV-1 RNA 100,000 copies/mL) who were followed for a median 112 weeks. The NRTI of choice was ZDV 42%, d4T XR 24%, and TDF 34%. Median baseline values were not different by arm: trunk fat 8.2 kg, extremity fat 7.0 kg, total cholesterol (TC) 154 mg/dL, HDL 35 mg/dL, non-HDL 117 mg/dL, and triglycerides (TG) 116 mg/dL. By week 96, 10%, 12%, and 26% of EFV, LPV, and LPV/EFV subjects used a lipid-lowering agent. Week-96 results (see the table) were similar to other time points. Lipoatrophy in the EFV or LPV+NRTI was predominately seen in the d4T- or ZDV-containing regimens; there was no significant difference (p >0.5) in lipoatrophy between TDF- containing and NRTI-sparing regimens.
Conclusions: A NRTI-sparing regimen (LPV+EFV) increased lipids significantly more than EFV or LPV+2 NRTI regimens. Triglyceride increases were also greater in LPV compared to EFV+NRTI regimens, but cholesterol changes were not significantly different. Compared to EFV, LPV had less lipoatrophy when given with NRTI. The frequency of lipoatrophy was lowest in NRTI-sparing and TDF-containing regimens.
Significant sparing of peripheral lipoatrophy by HIV treatment with LPV/r + ZDV/3TC induction followed by LPV/r monotherapy compared to EFV+ZDV/3TC
In this second presentation by Cameron et al, similar findings were reported. In Study 613 ART-naive patients received LPV/r SGC (400/100) bid + AZT/3TC (n=104) or EFV + AZT/3TC (n=51). Patients who received Kaletra were detensified to Kaletra monotherapy if at week 24 HIV RNA was <50 on 3 consecutive months, or remained on Kaletra+AZT/3TC. Dexa scans were obtained at baseline and every 24 weeks thereafter. The prevalence of lipoatrophy (>20% decrease in limb fat mass) and lipohypertrophy (>20% increase in trunk fat mass) at Week 96 was compared between groups using Fisher's exact test. Limb fat was average of 8.2 kg at baseline in LPV/r patients and 7.4 kg in EFV recipients. Trunk fat was 9.3 kg for LPV/r, and 8.3 for EFV. At week 96, 5% receiving Kaletra monotherapy had lipoatrophy and 34% taking EFV had lipoatrophy (p<0.001). Lipohypertrophy was the same in both groups, 45%. 16% in EFV group had both while 0 in Kaletra group had both. There was about a 15% increase in limb fat at week 96 compared to baseline for patients taking Kaletra compared to a 10% decrease in limb fat from baseline for patients taking EFV. The difference in fat at week 96 between the two groups was about 2.3 kg. Anthropomorphic changes were modestly but significantly correlated with DEXA measurements.
Cameron summarized:
"We noted a significant sparing of peripheral fat loss for a LPV/r induction-maintenance strategy compared to EFV + ZDV/3TC
This could be the result of reduced exposure to NRTIs, impact of EFV, or combination of both"
"These data complement data from ACTG 5142, in which LPV/r was associated with less fat loss compared to EFV regardless of NRTI used"
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