Current treatment guidelines for highly active antiretroviral treatment (HAART) include a boosted protease inhibitor (PI) as an option for first-line treatment of HIV-infected patients. However, it is well known that use of HAART is associated with various lipid abnormalities that may increase the risk of cardiovascular disease in HIV patients.

As part of a 24-week interim analysis of the ongoing 48-week Gemini trial, researchers assessed the percentage of patients (n=337) with abnormal lipids using a variety of measures in order 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 (Truvada) [(FTC/TDF] QD. The SQV formulation used was the Invirase 500mg tablet boosted with ritonavir 100mg, both dosed BID.

Results of the impact on lipid profiles were presented in poster (abstract) TuPeB069 by Dr. Sharon Walmsey and colleagues at the 4^th International AIDS Society (4^th IAS) conference in Sydney, AU (July 22-25, 2007).

The complete efficacy analysis will assess the non-inferiority of SQV/r compared with LPV/r at 48 weeks using the percentage of patients with viral load <400 copies /mL and <50 copies/mL, median increases in CD4 cells/mm3, and percentage of patients experiencing virologic failure (defined as any 2 consecutive HIV-1 RNA measurements, taken >/=14 days apart, >400 c/mL, at >/=16 weeks). The present planned interim analysis includes all patients completing 24 weeks of treatment. Results from the efficacy analysis of this study were presented at the 4^th IAS conference by Dr. Francois Raffi and colleagues in poster (abstract) WePeB027.

Study participants with HIV RNA >10,000 c/mL and >/= 350 CD4 cells/mm3 were randomized to SQV/r 1000/100 mg BID (n =166) or LPV/r 400/100 mg BID (n=171) plus FTC/TDF 200/300 mg QD for 48 weeks. The 24-week results presented this week at the Sydney conference are the second of two planned interim analyses.

Primary (Efficacy) Endpoints

• The primary efficacy endpoint for this study was the number and percentage of patients with an HIV-1 RNA viral load <50 copies/mL at week 48.

• The endpoints reported in the 24-week interim analysis were:

– the percentage of patients with an HIV-1 RNA viral load <50 copies/mL at week 24;

– change from baseline in plasma HIV-1 RNA viral load (copies/mL) at week 24;

– change from baseline in CD4+ lymphocyte count at week 24;

– number and percentage of patients discontinuing study medication due to clinical adverse events (including clinically significant laboratory abnormalities and AIDS Clinical Trial Group Grade ≥2 laboratory toxicities) at week 24.

Secondary (Safety) Endpoints

• 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.

• 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.

• Proportion of patients discontinuing study medication due to clinical adverse events (AEs) at week 24 (including clinically significant laboratory abnormalities and ACTG Grade ≥2 laboratory toxicities).

Safety Results

• 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)

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.

Figure 1

 Table 2

• 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.

– For TC, the percentage of patients with levels ≥200 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 ≥100 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 ≥400 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, the researchers stratified patients by

lipid increases of 1.15-, 1.3-, and 1.5-fold baseline values.

– 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.

Efficacy Results

• A total of 163 of the 166 patients randomized to SQV/r and 168 of the 171 patients randomized to LPV/r were included in the safety analysis.

• Demographic and disease baseline characteristics were similar in the two treatment groups (see Table 1 in attached poster).

• A similar proportion of patients in the SQV/r and LPV/r arms achieved undetectable HIV-1 RNA levels (<50 copies/mL) and levels of <400 copies/mL at all time points during the first 24 weeks of treatment (see Figure 1 in attached poster).

• The rate and extent of HIV-1 viral load reduction were similar in the SQV/r and LPV/r arms at all time points during the first 24 weeks of the trial (see Figure 2 in attached poster).

– At week 24, the median change (range) from baseline in HIV-1 RNA (log10 copies/mL) was nearly identical at –3.4 (–4.5 – 0.6) vs –3.5 (–4.8 – –0.8) in the SQV/r and LPV/r arms, respectively (see Figure 2 in attached poster).

– At week 24, the percentage of patients with a <–1.0 log10 (HIV-1 RNA copies/mL) change from baseline was ≥97.9% in both SQV/r and LPV/r arms.

• The rate and extent of increases in CD4 lymphocyte counts were comparable in the SQV/r and LPV/r arms at all time points during the first 24 weeks of the trial (see Figure 3 in attached poster).

– At week 24, the median change (range) from baseline in CD4 counts was 127 (–71–660) vs 135 (–39.0–604) in the SQV/r and LPV/r arms, respectively (see Figure 3 in poster).

Discontinuations

• The overall numbers of discontinuations in each study group were comparable (see Table 4 in attached poster).

• Of the 3 deaths that occurred during this study, only 1(hepatic failure in the LPV/r group) was considered to be possibly related to study treatment.

Virologic Failures

• Virological failure (VF) was observed in 10 patients (6%) receiving SQV/r and 3 patients (1.8%) receiving LPV/r. Most VFs were related to adherence. Only 2 of the patients who developed VF (both in the SQV/r arm) developed new PI mutations during the study.

Summary

Efficacy

Efficacy results showed that 69.9 percent and 69 percent of patients, respectively, treated with Invirase/ritonavir (r) (n=166) and lopinavir/r (n=171) achieved undetectable HIV levels (less than 50 copies per mL of blood; ITT analysis). The same proportion of patients (81.3 percent) in both groups achieved undetectable of less 400 copies per mL of blood. Furthermore, the rate and extent of increases in CD4 counts were comparable in both groups, with a median increase from baseline of 127 cells per cubic mL of blood for patients in the Invirase/r group, and 134 cells for patients in the lopinavir/r group.

Lipid Analysis

A total of 163 patients in the Invirase/r group and 168 patients in the lopinavir/r group were included in the safety analysis. At 24 weeks, patients treated with Invirase/r showed a lower median increase in their total cholesterol (TC) and total triglycerides (TG) than patients treated with lopinavir/r (increase of 17 versus 26 mg/dL for TC, and an increase of 14 versus 43 mg/dL for TG).

In addition, there was a trend toward fewer Invirase/r-treated patients who experienced an increase in their lipid profiles, above those recommended by the National Cholesterol Education Program and ACTG guidelines, than those treated with lopinavir/r.

In the Invirase/r group, the proportion of patients with TC levels above those recommended in guidelines was 21.5 vs. 26.8 percent for the lopinavir/r group; for LDL levels, 49.7 vs. 40.5 percent; and in TG levels, 1.2 vs. 8.9 percent. In the Invirase/r group, five patients withdrew due to adverse events, and in the lopinavir/r group, 11 patients withdrew due to adverse events.

Conclusions

In their conclusion, the study authors state, “In this 24-week interim analysis, treatment with SQV/r BID plus FTC/TDF QD was comparable to that with LPV/r BID plus FTC/TDF QD in terms of virological suppression and increases in CD4 cells.”

Both treatments were well tolerated, “although the mean increase of triglycerides is lower and fewer patients in the SQV/r arm experienced an increase in their lipid grades as evaluated by the NCEP (National Cholesterol Education Program) guidelines.”

In addition, the authors write, “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.”

Finally, they state, “The effectiveness of SQV/r BID vs LPV/r BID plus FTC/TDF QD as initial therapy in HIV-1-infected patients will be affirmed in the 48-week analysis of the Gemini trial.”

Commentary

“The full interim results from the Gemini study….suggest that boosted Invirase may be a good choice for many patients, particularly those with increased cardiovascular risk,” said Dr. Jihad Slim, Infectious Disease Specialist, St. Michael’s Medical Centre and an investigator in the Gemini study. “We need to be able to offer safer options for patients on combination HIV therapy – and establishing a PI-based regimen that is associated with fewer lipid abnormalities could have a real impact on HIV management.”

07/24/07

References

1. S Walmsley, U Bredeek, A Avihingsanon, and others. Evaluation of the impact of highly active antiretroviral therapy (HAART) on lipid profiles – data from the 24-week interim analysis of the Gemini Study: saquinavir/r (SQV/r) BID vs lopinavir/r (LPV/r) BID plus emtricitabine/tenofovir (FTC/TDF) QD in ARV-naοve HIV-1-infected patients. 4^th IAS. July 22-25, 2007. Sydney, AU. Abstract TuPeB069.

Presenting author email: sharon.walsmley@uhn.on.ca

University of Toronto, Medicine, Toronto, Canada, El Rio, Special Immunology Associates, Tucson, United States, HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, 4St Michael's Medical Center, Newark, United States, Roche, Nutley, United States

2. F Raffi, D Ward, K Ruxrungtham, and others. Saquinavir/r (SQV/r) BID vs lopinavir/r (LPV/r) BID plus emtricitabine/tenofovir (FTC/TDF) QD as initial therapy in HIV-1 infected patients: the Gemini Study. 4^th IAS. July 22-25, 2007. Sydney, AU. Abstract WePeB027. Presented by Francois Raffi, University Hospital, Nantes, France.

University Hospital, Nantes, France, Dupont Circle Physicians Group, Washington DC, United States, HIV-NAT, Thai Red Cross AIDS Research Centre, Bangkok, Thailand, Maple Leaf Medical Clinic, Toronto, Canada, Roche, Nutley, United States.

4th IAS
Main Conference Page