Effects of nucleoside analogues versus ritonavir boosted protease inhibitors on lipid levels – analysis of 12 clinical trials in 4231 antiretroviral naïve patients

Andrew Hill, Pharmacology Research Laboratories, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK, e-mail: microhaart@aol.com

Will Sawyer, South East Asian Research Collaboration with Hawaii (SEARCH), Bangkok, Thailand.

Brian Gazzard, Chelsea and Westminster Hospital, London.

Methods

The aim of this analysis was to estimate the effect of different ritonavir boosted protease inhibitors on lipids in naïve patients, using a standardised format to report lipid elevations.

To be included in the analysis, clinical trials needed to include (i) at least 50 antiretroviral naïve patients studied for at least 48 weeks (ii) use of a ritonavir boosted protease inhibitor (using a total daily ritonavir dose of 100 - 200mg), in combination with a fixed pair of nucleoside analogues, and (iii) with data available on mean levels of total cholesterol, triglycerides, LDL and HDL at baseline and at Week 48.

In multivariate analysis using inverse variance weighting and analysis of covariance, the relative effects on lipid parameters from the protease inhibitors versus the nucleoside analogues were assessed. The percentage rises in lipid parameters in the atazanavir/ritonavir and lopinavir/ritonavir arms of the CASTLE trial were used in a sensitivity analysis. The analysis was performed using Statistical Analysis Software (SAS).

Results

Clinical Trials References:

THE UNIVERSITY of LIVERPOOL

Conclusions:

Table 1 shows a summary of the 12 clinical trials included in the analysis. Mean levels of the four lipid parameters at baseline and week 48 are shown in Table 2. The percentage of patients using lipid lowering drugs was 4.5% in the SHARE trial [Elion 2007], 11% in the KLEAN trial [Eron 2006], 5% in the GEMINI trial [Walmsley 2007], and 2.6% in the ABT-418 trial [Johnson 2006].

In multivariate analysis, there was no significant difference in lipid elevations between either saquinavir, darunavir or atazanavir when boosted with ritonavir. Also there was no significant difference in lipid elevations between fosamprenavir-ritonavir and lopinavir- ritonavir.

For the nucleoside analogues, there was no significant difference in lipid elevations seen between abacavir or stavudine when given with lamivudine.

Figure 1 shows the mean percentage rises in the four lipid parameters, for the combined data from each ritonavir-boosted protease inhibitor, stratified for the use of either tenofovir/emtricitabine or other nucleoside analogues.

Summary results from the multivariate analysis are shown in Table 3. For total cholesterol and triglycerides, the rises were greater for trials of LPV/r and FPV/r, relative to those using ATV/r, DRV/r or SQV/r (p<0.001).

However the use of either d4T or abacavir as NRTIs also led to higher elevations in total cholesterol and triglycerides, relative to the use of tenofovir (p<0.001). For HDL and LDL, there was no evidence for differences between the boosted PIs. The confidence intervals around estimates of change were wide for both parameters, for each of the PIs.

There was also evidence for greater rises in both LDL and HDL for patients taking either abacavir/lamivudine or stavudine/lamivudine, relative to those using tenofovir/emtricitabine (p<0.001). This result was similar when all d4T data was excluded from the analysis (p<0.001).

The comparison of results from the multivariate analysis of the 12 trials versus the equivalent lipids data from the CASTLE trial is also shown in Figures 2-4. The mean percentage rises in total cholesterol, triglycerides and LDL were very similar for the atazanavir/ritonavir and lopinavir/ritonavir arms of the CASTLE trial, compared with the equivalent treatment groups in the multivariate analysis. The mean rises in HDL both the ATV/r and LPV/r treatment arms of the CASTLE trial appeared higher than for the multivariate analysis.

This meta-analysis of 12 clinical trials of first-line HAART in 4231 antiretroviral naïve patients suggests that both the choice of both protease inhibitor and nucleoside backbone can affect lipid elevations.

Those receiving lopinavir-ritonavir or fosamprenavir-ritonavir showed significantly greater rises in total cholesterol and triglycerides than use of the other three ritonavir boosted proteases – saquinavir, darunavir or atazanavir. Rises in LDL and HDL did not differ by choice of PI.

The use of either abacavir-lamivudine or stavudine-lamivudine also led to significantly greater rises in all four lipid parameters by week 48 than the use of tenofovir-emtricitabine.

The lipid rises seen after 48 weeks of treatment with TDF/FTC plus either DRV/r, ATV/r or SQV/r in the meta-analysis were very similar to those seen for TDF/FTC plus ATV/r in the CASTLE trial. This observation is consistent with the head-to head comparisons of lipids for DRV/r and ATV/r in a study of healthy volunteers (C159).

Abbott 418: Johnson et al. J Acquir Immune Defic Syndr 2006, 43: 153-160Abbott 863: Walmsley et al: N Engl J Med 2001, 346:2039-2046Abbott-730: Gathe J et al. 15th CROI, February 2008, Boston, USA [abstract 775]ALERT: Smith K et al. 4th IAS Conference, Sydney, Australia, July 2007: [abstract WEPEB023]ARTEMIS: DeJesus E et al. ICAAC, Chicago, USA September 2007 [abstract H-718b]BMS-089: Malan N et al. 13th CROI, Denver, Colorado, February 2006 [abstract]CASTLE: Molina J et al. 15th CROI, February 2008, Boston, USA [abstract 37]GEMINI: Walmsley S et al. 11th EACS Conference, Madrid, Spain, October 2007 [abstract PS1/4]HEAT: Smith K et al. 15th CROI, Boston, USA, February 2008 [abstract 774]KLEAN: Eron J et al. Lancet 2006, 368: 476-482, 2006.REDUCE: Hicks C et al: 11th EACS Conference, Madrid, Spain, October 2007 [abstract PS 7.01]SHARE: Elion R et al. 4th IAS Conference, Sydney, Australia, July 2007 [abstract WEPEB033]SOLO : Gathe J et al. AIDS 2004, 18: 1529-1537TMC114-C159: Tomaka F et al. HIV DART, Cancun, Mexico, December 2006. [abstract 85]

Figure 1: Multivariate analysis of percentage change in lipids fFigure 1: Multivariate analysis of percentage change in lipids from rom

baseline to week 48: Effects of NRTI versus PI usedbaseline to week 48: Effects of NRTI versus PI used

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Figure 2. Comparison of lipids data for DRV/r, ATV/r or SQV/r inFigure 2. Comparison of lipids data for DRV/r, ATV/r or SQV/r inmetameta--analysis (used with TDF/FTC), analysis (used with TDF/FTC), versus ATV/r arm of CASTLE trialversus ATV/r arm of CASTLE trial

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Figure 3. Comparison of lipids data for LPV/r or Figure 3. Comparison of lipids data for LPV/r or fAPV/rfAPV/rin metain meta--analysis (used with TDF/FTC), analysis (used with TDF/FTC), versus LPV/r arm of CASTLE trialversus LPV/r arm of CASTLE trial

Figure 4: Comparison of DRV/r arm of ARTEMIS trialFigure 4: Comparison of DRV/r arm of ARTEMIS trial

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THPE0167

XVII World AIDS Conference, Mexico City, August 2008 [THPE0167]