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

Abstract

The genotypic inhibitory quotient (GIQ) has been proposed as a way to integrate drug exposure and genotypic resistance to protease inhibitors and can be useful to enhance the predictivity of virologic response for boosted protease inhibitors. The aim of this study was to evaluate the predictivity of the GIQ in 116 protease inhibitor-experienced patients treated with lopinavir-ritonavir. The overall decrease in human immunodeficiency virus type 1 (HIV-1) RNA from baseline to month 6 was a median of ؊1.50 log 10 copies/ml and 40% of patients had plasma HIV-1 RNA below 400 copies/ml at month 6. The overall median lopinavir study-state C min concentration was 5,856 ng/ml. Using univariate linear regression analyses, both lopinavir GIQ and the number of baseline lopinavir mutations were highly associated with virologic response through 6 months. In the multivariate analysis, only lopinavir GIQ, baseline HIV RNA, and the number of prior protease inhibitors were significantly associated with response. When the analysis was limited to patients with more highly mutant viruses (three or more lopinavir mutations), only lopinavir GIQ remained significantly associated with virologic response. This study suggests that GIQ could be a better predictor of the virologic response than virological (genotype) or pharmacological (minimal plasma concentration) approaches used separately, especially among patients with at least three protease inhibitor resistance mutations. Therapeutic drug monitoring for patients treated by lopinavir-ritonavir would likely be most useful in patients with substantially resistant viruses.The development of human immunodeficiency virus (HIV) drug resistance during antiretroviral therapy can compromise the efficacy of subsequent regimens following virologic failure. Several studies have shown that changes in baseline viral genotype, compared to that of wild-type virus, adversely affect the virologic response of antiretroviral-experienced subjects with a subsequent regimen (3,4,19). However, the efficacy of antiretroviral treatment can be impaired by several factors, including poor adherence to treatment regimens, suboptimal antiviral potency and/or drug concentrations, and of course selection of antiretrovirus agent-resistant HIV quasispecies.More information on the effect of these parameters should be beneficial for optimizing the use of protease inhibitors in salvage therapy. The inhibitory quotient, mainly used for the protease inhibitors, has been proposed as a way to integrate drug exposure and viral susceptibility. Defined as the ratio between the trough concentration of a drug in a patient and the susceptibility of the virus in that patient to that drug, the inhibitory quotient has been associated with virologic response to protease inhibitor-based antiretroviral therapy in several studies (6, 17;

Darunavir Inhibitory Quotient Predicts the 48-Week Virological Response to Darunavir-Based Salvage Therapy in Human Immunodeficiency Virus-Infected Protease Inhibitor-Experienced Patients

“…In agreement with reports for other protease inhibitors as well as for darunavir itself (1,9,10,(14)(15)(16) In those studies, the virological outcome of darunavir-based salvage therapy was much better predicted by the darunavir pIQ than by either the darunavir concentration or the change in the darunavir IC 50 alone. However, phenotypic resistance testing is complex and expensive in the clinical setting, and pIQ data may therefore not be available for a large proportion of patients outside clinical trials.…”

“…However, phenotypic resistance testing is complex and expensive in the clinical setting, and pIQ data may therefore not be available for a large proportion of patients outside clinical trials. The gIQ and vIQ are simpler to obtain than the pIQ and have been shown to predict virological response to salvage antiretroviral therapy with several protease inhibitors (1,9,10,(14)(15)(16).…”

Lopinavir Plasma Concentrations and Virological Outcome with Lopinavir-Ritonavir Monotherapy in HIV-1-Infected Patients

“…On the other hand, our data suggest that measurement of LPV concentrations is not useful for predicting virological outcome. There are several plausible explanations for the lack of this relationship, including that LPV C min was not the most correct pharmacodynamic parameter to evaluate its activity, as has been observed in highly antiretroviral agentexperienced subjects (16,18,25), or differences in susceptibility to LPV among the various viral isolates, although no subjects had major resistance mutations associated with reduced susceptibility to LPVr. However, we believe that the most plausible explanation might be the "white-coat compliance" phenomenon, in which adherence considerably improves even in subjects with poor adherence just prior to a study visit, especially if they know that pharmacokinetic sampling will be performed (26).…”

“…As LPV plasma concentrations and the genotype inhibitory quotient have been related to virological efficacy in experienced patients on LPVr-based regimens (16)(17)(18)(19), in this study, we tested whether low plasma LPV trough concentrations contribute to VF throughout the mtLPVr treatment period. The confirmation of this hypothesis would demonstrate that LPV therapeutic drug monitoring could be useful in improving the efficacy of LPV when prescribed as a monotherapy.…”

The Design and Implementation of A5146, a Prospective Trial Assessing the Utility of Therapeutic Drug Monitoring Using an Inhibitory Quotient in Antiretroviral-Experienced HIV-Infected Patients

“…There are a number of potential explanations for this result. First, this trial did not utilize an inhibitory quotient (IQ), which incorporates both drug exposure and viral drug resistance and has been shown in several studies to correlate with virologic responses in treatment-experienced patients [12][13][14][15][16][17][18][19][20][21][22][23] . Second, the majority of subjects in the TDM arm did not undergo a dose adjustment 11 .…”