- ABT-378/ritonavir and efavirenz for salvage therapy in patients multiply-exposed to PIs (TuPeB3196)
Authored by N. Clumek, P.M. Girard, A. Telenti, J. Rockstroh, S. Becker, A. Lazzarin, S. Brun, E. Sun, X.U. Yi
Some of the most exciting data presented at this meeting involved studies of ABT-378 (now known as lopinavir) that is co-formulated in the same capsule with a small dose of ritonavir, which significantly enhances lopinavir drug levels. The high blood levels of lopinavir that are achieved provide a pharmacologic barrier to the development of resistance and are responsible for lopinavir's activity against strains that are already resistant to protease inhibitors (PIs). This study included patients with multiple prior PI use (at least two PIs for three months each), a viral load greater than 1,000 copies on their current PI-containing regimen, and no prior use of an NNRTI.
Because efavirenz can lower PI blood levels, participants were randomized to the standard dose of lopinavir/ritonavir, 400mg/100mg twice a day, or to a higher dose, 533mg/133mg twice a day. Drug levels of both lopinavir and efavirenz were obtained. Fifty-seven patients with average of three prior PIs had phenotypic resistance testing at entry.
Sixty-eight percent had virus that were cross-resistant to at least three FDA-approved PIs (four-fold decrease in virus susceptibility), and 43% showed significant resistance (ten-fold or more decrease in susceptibility) to lopinavir.
Administration of standard-dose lopinavir with efavirenz resulted in about a 33% decrease in lopinavir levels, but the higher dose of lopinavir given with efavirenz resulted in the same blood levels achieved by lopinavir in the absence of efavirenz. Efavirenz levels were unaffected. As a result, all participants were switched to the higher dose.
Four patients withdrew before week 24 because of side effects and three because of virologic failure. The intent-to-treat analysis demonstrated that 82% of the 533/133 group and 69% of the 400/100 group had viral loads less than 400 copies at week 24. Despite extensive prior treatment with antiretrovirals, CD4 cells increased by an average of 381 and 295 cells for the higher and standard dose arms, respectively. Study therapy was well tolerated, and although cholesterol levels increased somewhat during the study, the increases were not significantly changed from entry. Despite high baseline levels of resistance to lopinavir and other PIs, the majority of patients achieved both viral suppression and significant increases in CD4 cells. Lopinavir plus efavirenz shows considerable promise as the basis of a salvage regimen for patients who have failed multiple PIs.