Human immunodeficiency virus type 1 genotypic and pharmacokinetic determinants of the virological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients

Abstract

The response to regimens including lopinavir-ritonavir (LPV/r) in patients who have received multiple protease (PR) inhibitors (PI) can be analyzed in terms of human immunodeficiency virus type 1 (HIV-1) genotypic and pharmacokinetic (pK) determinants. We studied these factors and the evolution of HIV-1 resistance in response to LPV/r in a prospective study of patients receiving LPV/r under a temporary authorization in Bordeaux, France. HIV-1 PR and reverse transcriptase sequences were determined at baseline LPV/r for all the patients and at month 3 (M3) and M6 in the absence of response to treatment. pK measurements were determined at M1 and M3. Virological failure (VF) was defined as a plasma viral load >or=400 copies/ml at M3. A multivariate analysis of the predictors of VF, including clinical and biological characteristics and the treatment history of the patients, was performed. The PR gene sequence at M0, including individual mutations or a previously defined LPV mutation score (D. J. Kempf, J. D. Isaacson, M. S. King, S. C. Brun, Y. Xu, K. Real, B. M. Bernstein, A. J. Japour, E. Sun, and R. A. Rode, J. Virol. 75:7262-7269, 2001), and the individual exposure to LPV were also included covariates. Sixty-eight patients were enrolled. Thirty-four percent had a virological response at M3. An LPV mutation score of >5 mutations, the presence of the PR I54V mutation at baseline, a high number of previous PIs, prior therapy with ritonavir or indinavir, absence of coprescription of efavirenz, and a lower exposure to LPV or lower LPV trough concentrations were independently associated with VF on LPV/r. Additional PI resistance mutations, including primary mutation I50V, could be selected in patients failing on LPV/r. Genotypic and pK parameters should be used to optimize the virological response to LPV/r in PI-experienced patients and to avoid further viral evolution.

FIG. 1.

(A) Mutations in the HIV-1 protease in 66 patients at baseline therapy with LPV/r. Protease mutations are those reported by the IAS-USA panel (http://www.iasusa.org). LPV mutations, mutations included in the LPV mutation score, i.e., the number of baseline protease mutations out of 11 possible mutations: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/V/T, V82A/F/T, I84V, and L90 M; other R mutations, mutations not included in the LPV mutation score; % of patients, percentage of patients with the corresponding mutation at baseline LPV/r. (B) Mutations in the HIV-1 RT in 65 patients at baseline LPV/r. NRTI and NNRTI resistance mutations are those reported by the IAS-USA panel.

FIG. 2.

Virological response to LPV/r-containing regimens at M3 according to the LPV mutation score (n = 65). <400 copies/ml, patients with plasma HIV-1 RNA levels of <400 copies/ml at M3; <400 c/ml or −1log₁₀, patients with plasma HIV-1 RNA levels of <400 copies/ml at M3 and/or with a decrease of plasma HIV-1 RNA by >1 log₁₀ unit between M0 and M3; LPV mutation score, number of baseline protease mutations out of 11 mutations: L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/V/T, V82A/F/T, I84V, and L90M.