It is a common assumption that the most recently approved antiretroviral agents are more potent than their predecessors, but this is not always the case.

Interim data presented at the 8th International Congress on Drug Therapy in HIV Infection this week in Glasgow showed that ritonavir-boosted saquinavir (Invirase) suppressed HIV as well as lopinavir/ritonavir (Kaletra), one of the two boosted protease inhibitors (PIs) currently included as elements of a "preferred" antiretroviral regimen in the latest version of the DHHS HIV treatment guidelines.

Saquinavir, approved in late 1995, was one of the first two PIs marketed in the U.S., along with indinavir (Crixivan). The original Invirase hard-gel formulation had low bioavailability, prompting the development of a soft-gel formulation called Fortovase, which was better absorbed but still had a high pill burden. With the discovery that low doses of ritonavir (Norvir) could be used to boost blood levels of other PIs, Invirase once again became the preferred formulation and Fortovase was discontinued. However, some clinicians and patients remain reluctant to use saquinavir, regarding it as an "old" and suboptimal therapy.

As reported at the recent meeting, an international team of researchers conducted a Phase IIIb study called GEMINI -- sponsored by saquinavir manufacturer Roche -- in which 337 treatment-naive individuals were randomly assigned to receive either saquinavir 500 mg plus ritonavir 100 mg or else lopinavir/ritonavir (600/100 mg), both twice daily. All subjects also received the fixed-dose tenofovir/emtricitabine pill (Truvada).

Baseline characteristics were similar in both groups. About 55% were men and the median age was 36. The subjects had relatively advanced disease, with a median HIV RNA level of about 150,000 copies/mL and a mean CD4 cell count of about 125 cells/mm3 (nearly one-third with CD4 counts below 50 cells/mm3)

The study will continue through Week 48 of treatment; an interim analysis of data from 150 subjects who reached Week 24 were presented.

Results

After 24 weeks, in an intent-to-treat analysis, a similar proportion of patients in the saquinavir/ritonavir and lopinavir/ritonavir arms achieved undetectable (< 50 copies/mL) HIV viral load (69.4% vs 75.3%, respectively; P = 0.427).

The corresponding percentages with HIV RNA < 400 copies/mL were 80.6% and 83.6%.

In an as-treated analysis (counting only those subjects who stayed on their assigned therapy), the percentages with HIV RNA < 50 copies/mL were 79.4% and 85.9%, respectively.

5 patients in the saquinavir/ritonavir arm and 2 in the lopinavir/ritonavir arm experienced virological failure, defined as HIV RNA > 400 copies/mL after Week 16.

CD4 cell count increases were similar in both arms.

Lipid levels increased significantly more in the lopinavir/ritonavir arm compared with the saquinavir/ritonavir arm by Week 24:

- total cholesterol > 200 mg/dL: 38% vs 21%;
- triglycerides > 400 mg/dL: 13% vs 1%.

Gastrointestinal side effects (e.g., nausea, diarrhea) were more common in the lopinavir/ritonavir arm (23% vs 14%).

Grade 2-4 adverse events were common in both arms: 48% for saquinavir/ritonavir and 58% for lopinavir/ritonavir.

22% discontinued for any reason in both arms.

Adherence rates were similar in both arms (about 85%).

Conclusion

"These preliminary results suggest that boosted [saquinavir] has the power to control the virus in treatment-naive patients, while also managing their lipid profile," said lead author Jihad Slim, MD, of St. Michael's Medical Center in Newark, NJ. "If the final results show that boosted [saquinavir] maintains its ability to suppress the virus with a good lipid profile, it could become a preferred choice for some patients, especially those troubled by treatment side effects."

11/17/06

Sources

Slim, A Avihingsanon, K Ruxrungtham, and others. Saquinavir BID vs lopinavir plus emtricitabine/tenofovir QD in ARV-naive HIV-1 infected patients: GEMINI study. 8th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland. November 12-16, 2006. Abstract 2.5.

Roche. New Study Indicates Boosted Invirase 500 Patients Achieve Similar Levels of Viral Suppression to Boosted Lopinavir but with a Better Lipid Profile. Press release. November 13, 2006.