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  4th IAS (Intl AIDS Society) Conference on HIV Pathogenesis, Treatment and Prevention
Sydney, Australia
22-25 July 2007
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Saquinavir/r bid vs Kaletra bid GEMINI Study, 24 weeks Interim Lipids Analysis
 
 
  Evaluation of the impact of HAART on lipid profiles - data from the 24-week interim analysis of the Gemini Study: Saquinavir/r vs lopinavir/r plus emtricitabine/tenofovir in antiretroviral-naive HIV-1-infected patients
 
Reported by Jules Levin
4th IAS Conference on HIV Pathogenesis, Treatment and Prevention
22-25 July 2007 Sydney, Australia
Poster TuPeB069
 
S Walmsley,1 UF Bredeek,2 A Avihingsanon,3 J Slim,4 and CJ Guittari5 1University of Toronto, Toronto, Canada; 2El Rio, Special Immunology Associates, Tucson, AZ, USA; 3HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; 4St Michael's Medical Center, Newark, NJ, USA; 5Roche, Nutley, NJ, USA
 
Analysis of the effects of PIs on hyperlipidemia is important for assessing the overall safety of treatment with PIs and is best analyzed in a prospective, controlled, randomized study.
 
Although PIs have been associated with lipid elevations, recent data also have shown hyperlipidemia to be associated with certain nucleosides (especially thymidine analogs) and also with efavirenz.4
 
Since antiretroviral-naive participants, such as those enrolled in the Gemini Study, often have low cholesterol or lipid levels due to their disease status,5 treatment often normalizes these values. Therefore, evaluation of lipid changes from baseline alone is not an accurate measure of the clinical impact of the treatment regimen.
 
As part of a 24-week interim analysis of the ongoing 48-week Gemini Study, we assessed the percentage of patients with abnormal lipids using a variety of measures to more accurately measure the effects of treatment on lipids and cholesterol in patients treated with saquinavir/ritonavir (SQV/r) or lopinavir/ritonavir (LPV/r) BID, with both groups receiving emtricitabine/tenofovir (FTC/TDF) QD.
 
AUTHOR CONCLUSIONS
At 24 weeks, treatment with LPV/r was associated with a trend of greater hyperlipidemia than treatment with SQV/r.
 
The median increase in TC and TG was lower and occurred in fewer patients in the SQV/r arm than in the LPV/r arm.
 
Fewer patients in the SQV/r arm experienced an increase in their lipid levels above those recommended by the NCEP and ACTG guidelines. This difference was especially pronounced in patients with TC ³200 mg/dL or TG ³400 mg/dL.
 
The use of lipid-lowering agents was comparable between the two arms, with higher fibrate use in the LPV/r group possibly a reflection of the increased TG levels observed in LPV-treated patients.
 
The differences between arms need to be confirmed in the final 48-week analysis and should be considered in the context of other cardiac risk factors when choosing a treatment regimen.
 
Study Design
Prospective, Phase IIIb, randomized, multicenter, open-label, two-arm, 48-week study in the USA, Canada, Puerto Rico, France, and Thailand.
 
Antiretroviral treatment-naive patients were randomized 1:1 to SQV/r 1000/100 mg BID or LPV/r 400/100 mg BID, plus FTC/TDF 200/300 mg QD for 24 weeks in this planned interim analysis.
 
Safety/Lipids
It has been suggested that National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guideline cutpoints for low-density lipoprotein (LDL) and AIDS Clinical Trials Group (ACTG) guideline cutpoints for total cholesterol (TC) and triglycerides (TGs) are a clinically relevant measure of lipid parameters.7,8
 
Therefore, changes in lipid parameters in patients treated with SQV/r vs LPV/r plus FTC/TDF were measured by:
- change from baseline for TC, LDL, high-density lipoprotein (HDL), and TG
- a post hoc analysis of the proportion of patients with lipid parameter levels greater than NCEP ATP III and ACTG guidelines
- a post hoc analysis of the proportion of patients with lipid increases of 1.15-, 1.3-, and 1.5-fold baseline values. These strata were based on those used previously by the US FDA.9
 
Proportion of patients discontinuing study medication due to clinical adverse events (AEs) at week 24 (including clinically significant laboratory abnormalities and ACTG Grade ³2 laboratory toxicities).
 
Statistical Method for Interim Analysis
Summary statistics such as the number and the percentage of patients are presented by treatment group. For change from baseline, statistics such as mean, standard deviation, median, and minimum and maximum values are also presented by treatment group.
 
Median values are reported for endpoints with skewed distributions (as determined by Skilman-Wilson test).
 
Results
 
Patient Disposition

The safety analysis included 163 of 166 patients who were randomized to SQV/r and 168 of 171 patients randomized to LPV/r.
 
Through 24 weeks of the study, 27 and 25 patients withdrew from the study in the SQV/r and LPV/r groups, respectively.
 
The reasons for withdrawal were:
-- AEs (5 vs 11 for SQV/r and LPV/r, respectively)
-- deaths (2 vs 1 for SQV/r and LPV/r, respectively)
-- non-safety causes that included insufficient therapeutic response, violation of protocol, refusal of treatment, or failure to return for evaluations.
 
Demographics and Baseline Disease
Characteristics

Demographics and baseline disease characteristics were comparable between groups (Table 1).
 

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Lipid Analysis
The median changes from baseline for TC, LDL, HDL and TG are shown in Figure 1 and Table 2.
-- At 24 weeks, the median increases for TC and TG were lower in the SQV/r arm compared with the LPV/r arm.
 

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A lower percentage of patients in the SQV/r arm compared with the LPV/r arm experienced an increase in cholesterol and TG to levels above those recommended by ACTG guidelines whereas a higher percentage experienced an increase in LDL levels above those recommended by NCEP guidelines (Table 3, Figure 2).
-- For TC, the percentage of patients with levels ³200 mg/dL at week 24 was 21.5% in the SQV/r arm and 26.8% in the LPV/r arm.
-- For LDL, the percentage of patients with levels ³100 mg/dL at week 24 was similar for both arms; 49.7% of patients in the SQV/r arm to 40.5 % in the LPV/r arm.
-- For TG, the percentage of patients with levels ³400 mg/dL at week 24 was 1.2% in the SQV/r and 8.9% in the LPV/r arm. -- Both regimens had comparable improvements in HDL levels.
 
To further elucidate these findings, we stratified patients by lipid increases of 1.15-, 1.3-, and 1.5-fold baseline values (Figure 3).
-- The percentage of patients with increases from baseline in TC was greater for the LPV/r arm than the SQV/r arm.
-- The percentage of patients with increases from baseline in TG was higher in the LPV/r arm compared with the SQV/r arm, with the greatest increases in patients with >1.5 times the baseline value.
 
Lipid-lowering Agents Used by Study Participants
Lipid-lowering agents were used by 5 and 6 participants in the SQV/r and LPV/r arms, respectively.
 
In the SQV/r arm:
-- 5 participants used statins (4 atorvastatin, 1 rosuvastatin).
 
In the LPV/r arm:
-- 1 participant used a statin (atorvastatin)
-- 4 participants used fibrates (3 gemfibrozil, 1 ciprofibrate)
-- 1 participant used a basic ion exchange resin (colestyramine).
 

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Only 1 participant in the SQV/r arm and 2 participants in the LPV/r arm were known to be receiving lipid-lowering agents prior to study entry. This datum is unavailable for 1 participant in the LPV/r arm.
 
References
1. Hammer SM, Saag MS, Schechter M, et al. JAMA 2006;296:827-843.
2. The EACS Executive Committee 2005. Available at http://www. eacs.ws/guide/m_guides.htm (accessed 27 June 2007).
3. Koppel K, Bratt G, Eriksson M, Sandstrom E. Int J STD AIDS 2000;11:451-455.
4. Barragan P, Fisac C, Podzamczer D. AIDS Rev 2006;8:191-203.
5. Haubrich RH, Riddler S, DiRienzo G, et al. Presented at 14th Conference on retroviruses and Opportunistic Infections, 25-28 February 2007, Los Angeles, CA, USA. Abstract 38.
6. Raffi F, Ward D, Ruxrungtham K, Brunetta J, Schutz M. Presented at 4th IAS Conference on HIV Pathogenesis, Treatment and Prevention, 22-25 July 2007, Sydney, Australia. Abstract WePeB027.
7. National Cholesterol Education Program (NCEP) Expert Panel. Availabl at http://www.nhlbi.nih.gov/guidelines/cholesterol/index.htm (accessed 27 June 2007).
8. Dube MP, Sprecher D, Henry WK, et al. Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clin Infect Dis 2000;31:1216-1224. 9. Proestel S. Available at http://www.fda.gov/ohrms/dockets/ac/07/ slides/2007-4283s1-02-02-FDA_Proestel_files/frame.htm (accessed 27 June 2007).