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 >400 copies/ml at M3. , 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. Treatment of human immunodeficiency virus (HIV)-in-fected individuals with combination therapy including protease inhibitors (PI) results in a significant suppression of HIV replication (1, 2, 3, 11) and in improvement in clinical outcomes, with marked reductions in HIV-associated morbidity and mortality (5, 9). However, the efficacy of antiretroviral (ARV) treatment can be impaired by several factors, including poor compliance with treatment regimens, suboptimal antiviral potency and drug concentrations, and selection of ARV-resistant HIV quasispecies (6). Resistance to PI is driven by the selection of primary mutations located close to the active site of the HIV type 1 (HIV-1) protease, producing significant changes in the affinity of the binding of the inhibitor to the mutant active site (4) and often occurs early during virological rebound. Secondary resistance mutations may be selected later and may compensate for the initial decrease of viral fitness related to the appearance of primary mutations. These secondary mutations tend to be common to all PI, facilitating the emergence of resistance to the whole PI class.Lopinavir (LPV)-ritonavir (LPV/r) is a coformulation of lopinavir, an HIV PI, and low-dose ritonavir, which inhibits LPV metabolism and which enhances plasma LPV levels (12). LPV/r has shown significant potency in treatment-naive and in PI-experienced patients. Few data concerning the determinants and the emergence of drug resistance in LPV/r-treated patients are available. In the LPV/r arm of a first-line ARV therapy protocol, all virological fa...

Virological and Pharmacological Parameters Predicting the Response to Lopinavir-Ritonavir in Heavily Protease Inhibitor-Experienced Patients

“…This efficacy of lopinavir-ritonavir in protease inhibitor experienced patients was observed previously in clinical trials or in other expanded access datasets and in the whole cohort of 792 patients (8,13) In the current retrospective analysis, we demonstrated that inhibitory quotient evaluated using genotypic test results was a better predictor of the virologic response than virological (genotype) or pharmacological (C min ) approaches used separately, especially among patients with at least 3 protease inhibitor resistance mutations. The observation of predictivity of the GIQ, even among patients with substantially reduced genotypic susceptibility to lopinavir-ritonavir, is in accordance with its pharmacokinetic profile, in which mean trough levels (5,500 ng/ml) are sustained far above (Ͼ75-fold when dosed at 400/ 100 mg twice-daily) the human serum-adjusted 50% inhibitory concentration for wild-type virus (inhibitory quotient Ͼ 75).…”

In Vitro Hypersusceptibility of Human Immunodeficiency Virus Type 1 Subtype C Protease to Lopinavir

“…Interestingly, this effect was not observed when clone C5 was tested, implicating an association of the I93L mutation with this phenotype. It is notable that this mutation was previously reported to be associated with isolates from patients who had failed lopinavir therapy in clinical trials in which individuals infected with subtype B were studied (14). We could not observe any difference in the IC 50 s of the other commercially available PIs tested when the IC 50 s for these two clones were compared to those for strain HXB2/NL4-3-PR.…”

Selection of Resistance in Protease Inhibitor-Experienced, Human Immunodeficiency Virus Type 1-Infected Subjects Failing Lopinavir- and Ritonavir-Based Therapy: Mutation Patterns and Baseline Correlates

“…The present results provide insight into exploratory algorithms for LPV resistance, shown in Table 4, which are based either on the correlation of genotype and phenotype in the isolates from PI-experienced patients (22,31,40) or the correlation of baseline genotype with virologic response in PIexperienced patients (17). In general, these algorithms have been shown to be predictive of the virologic response to LPV-RTV therapy in PI-experienced patients (8,17,21,25,35). All of the canonical PI mutations (15) emerging upon rebound in PI-experienced subjects in this study are contained in at least one algorithm, including L10I, K20M/R, L24I, L33F, M46I/L, G48V, I54V, and V82A, which appear in three or more of the four algorithms (Table 4).…”