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Twelve-Study Analysis Implicates Certain PIs and NRTIs in Lipid Jumps
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XVII International AIDS Conference
August 3-8, 2008
Mexico City
Mark Mascolini
A 12-study meta-analysis yielded evidence that ritonavir-boosted lopinavir or fosamprenavir unsettles lipids more than boosted atazanavir, darunavir, or saquinavir [1]. Among the nucleoside (NRTI) pairs analyzed, abacavir/lamivudine (ABC/3TC) and stavudine/lamivudine (d4T/3TC) upset lipids more than tenofovir/emtricitabine (TDF/FTC).
Andrew Hill (University of Liverpool) and colleagues scrutinized trials enrolling 4231 antiretroviral-naive people. All studies met three criteria: (1) at least 50 participants treated for at least 48 weeks, (2) a protease inhibitor (PI) boosted by 100 to 200 mg of ritonavir daily and a fixed double-nucleoside backbone, and (3) data on mean cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides before treatment and at 48 weeks.
The analysis included one trial of saquinavir/ritonavir plus TDF/FTC (GEMINI), one trial of darunavir/ritonavir plus TDF/FTC (ARTEMIS), three trials of atazanavir/ritonavir with TDF/3TC, ABC/3TC, or d4T/3TC (ALERT, SHARE, and BMS-089), four trials of fosamprenavir/ritonavir with TDF/FTC in one trial and ABC/3TC in three (ALERT, SOLO, KLEAN, and REDUCE), and seven trials of lopinavir/ritonavir with TDF/FTC in four, ABC/3TC in two, and d4T/3TC in one (ARTEMIS, GEMINI, ABT 418, ABT 730, HEAT, KLEAN, and ABT 863).
Multivariate analysis showed no significant lipid differences between three boosted PIs (saquinavir, darunavir, and atazanavir) or between fosamprenavir and lopinavir. Nor were there significant lipid differences between ABC and d4T when given with 3TC.
These analyses showed that both lopinavir and fosamprenavir pushed up total cholesterol and triglycerides significantly more than the other three PIs (P < 0.001). And d4T- or ABC-containing regimens yielded higher concentrations of total cholesterol and triglycerides than TDF-containing regimens (P < 0.001). Both "bad" LDL cholesterol and "good" HDL cholesterol rose more in people taking ABC/3TC or d4T/3TC than in those taking TDF/FTC (P < 0.001). But different PI regimens did not have differing effects on HDL and LDL.
In a sensitivity analysis, lipid jumps after 48 weeks of TDF/FTC plus either darunavir/ritonavir, atazanavir/ritonavir, or saquinavir/ritonavir were similar to those recorded with TDF/FTC plus atazanavir/ritonavir in the CASTLE trial.
Although analyses combining results from diverse trials are fraught with limitations (are data from a single saquinavir trial as revealing as data from seven lopinavir trials?), they can yield at least global hints of relative side effect rates. The abacavir results are interesting in light of two recent studies linking that drug to a higher relative risk of cardiovascular disease [2,3].
References
1. Hill A, Sawyer W, Gazzard B. Effect of nucleoside analogues versus ritonavir boosted protease inhibitors on lipid levels--analysis of 12 clinical trials in 4231 antiretroviral-naive patients. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THPE0167.
2. D:A:D Study Group. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the D:A:D study. Lancet. 2008;371:1417-1426.
3. Lundgren J, Neuhaus J, Babiker A, et al. Use of nucleoside reverse transcriptase inhibitors and risk of myocardial infarction in HIV-infected patients enrolled in the SMART study. XVII International AIDS Conference. August 3-8, 2008. Mexico City. Abstract THAB0305.
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