Disease relevance of Aluviran

• INTRODUCTION: Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir [1].
• RESULTS: At baseline (n=37), the median CD4+ cell count was 207/mm3 and the median plasma HIV-1 RNA level was 4.7 log10 copies/ml; the median number of PI mutations was seven and the median decrease in phenotypic susceptibility to lopinavir and amprenavir was 9.7 and 2.6, respectively [2].
• High rate of proV47A selection in HIV-2 patients failing lopinavir-based HAART [3].
• OBJECTIVE:: To determine whether the level of persistent HIV-1 viremia is affected by simplifying standard antiretroviral therapy to lopinavir/ritonavir (LPV/r) alone [4].
• Remission of HIV-associated myelopathy after initiation of lopinavir in a patient with extensive previous exposure to highly active antiretroviral therapy [5].

High impact information on Aluviran

• Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children [1].
• We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children [1].
• To examine the capacity of HIV-1 to adapt to these treatment changes, we have followed the evolution of HIV-1 protease genotypes and phenotypes in 21 protease-inhibitor-experienced patients in whom 26 weeks of an aggressive salvage regimen associating lopinavir, amprenavir and ritonavir failed to suppress viral replication [6].
• Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data [1].
• METHODS: HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115mg/m2 once daily with zidovudine and lamivudine [1].

Chemical compound and disease context of Aluviran

• The combination of lopinavir/ritonavir and efavirenz suppressed HIV-1 levels for a prolonged period and resulted in a significant increase in CD4+ T cell numbers despite an extensive prior treatment with NRTI (>4 years) [7].
• Preliminary results are presented from a dose-comparison trial of the regimen stavudine/lamivudine plus the novel protease inhibitor, ABT-378/ritonavir, given to 101 antiretroviral-naive, human immunodeficiency virus (HIV)-infected subjects for > or = 24 weeks [8].
• BACKGROUND:: The HIV protease inhibitor (PI) atazanavir does not impair insulin sensitivity acutely but ritonavir and lopinavir induce insulin resistance at therapeutic concentrations [9].
• METHODS: Eligible patients with plasma HIV-1 RNA > 5000 copies/ml received ABT-378 200 or 400 mg with ritonavir 100 mg every 12 h; after 3 weeks stavudine 40 mg and lamivudine 150 mg every 12 h were added (group I, n = 32) [10].
• Only patients with very high body weight presented lopinavir and saquinavir concentrations lower than the overall group [11].

Biological context of Aluviran

• We confirmed that a 10-fold increase of lopinavir IC50 is an appropriate clinical cut-off for lopinavir vPhenotype [12].
• Drug interaction between amprenavir and lopinavir/ritonavir in salvage therapy [13].
• CONCLUSION: Lopinavir/ritonavir decreases the AUC of lamotrigine, probably by induction of glucuronidation [14].
• Over the course of 48 weeks, median predose concentrations of lopinavir exceeded the protein-binding corrected concentration required to inhibit replication of wild-type HIV by 50% in vitro by 40- and 84-fold in the once- and twice-daily groups, respectively [15].
• Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content [16].

Anatomical context of Aluviran

• OBJECTIVE: To determine whether an association existed between lopinavir (LPV) plasma concentrations and changes in body fat composition [17].
• In contrast, lopinavir, saquinavir, and ritonavir inhibited the development of preadipocytes into adipocytes [18].
• In contrast, lopinavir (LPV) and amprenavir did not increase osteoclast activity [19].
• Limited penetration of lopinavir into seminal plasma of HIV-1-infected men [20].
• Prior anecdotal reports indicated that lopinavir concentrations were below detection in cerebrospinal fluid (CSF) [21].

Associations of Aluviran with other chemical compounds

• Atazanavir and lopinavir/ritonavir: pharmacokinetics, safety and efficacy of a promising double-boosted protease inhibitor regimen [22].
• METHODS: Adipocyte differentiation of mouse 3T3-F442A, 3T3-L1 and Ob1771 cells as well as embryonic stem cells were investigated at pharmacological concentrations of indinavir, saquinavir, ritonavir, amprenavir, nelfinavir and lopinavir [23].
• DESIGN: Prospective, cohort analysis of 1161 PI-naive, HIV-infected patients receiving RTV-boosted (lopinavir, indinavir and saquinavir) and unboosted PI-based ART (indinavir, nelfinavir) that had at least one liver enzyme measurement before and during therapy [24].
• In multivariate analysis, patients on lopinavir/ritonavir had the highest risk of developing elevated BP [odds ratio (OR), 2.5; P = 0.03] compared with efavirenz-based regimens [25].
• RESULTS:: Atazanavir inhibited glucose uptake in vitro significantly less than lopinavir and ritonavir at all concentrations [9].

Gene context of Aluviran

• This is consistent with mechanism-based inhibition of human CYP3A by lopinavir [26].
• Lopinavir produced negligible or weak inhibition of human CYP1A2, 2B6, 2C9, 2C19 and 2D6 [26].
• The effects of ritonavir and lopinavir/ritonavir on the pharmacokinetics of a novel CCR5 antagonist, aplaviroc, in healthy subjects [27].
• DRUG INTERACTIONS: Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes [16].
• Lopinavir, the active component of this combination, is extensively metabolized by CYP3A4 and produces low systemic concentrations when used alone [28].

Analytical, diagnostic and therapeutic context of Aluviran

• We evaluated the virological outcome of lopinavir/ritonavir (LPV/RTV) in 224 HIV-1-infected and protease inhibitor (PI)-experienced patients showing virological failure to a highly active antiretroviral therapy (HAART) regimen and followed up for at least 3 months [29].
• OBJECTIVE: To assess the rate of protocol-defined treatment failure and safety of lopinavir/ritonavir (LPV/r) and saquinavir/ritonavir (SAQ/r) [30].
• We showed by ELISA that two inhibitors of the HIV protease, lopinavir and ritonavir, accumulated at similar levels during the development of hMADS cells in adipocytes, whereas a non-nucleoside reverse transcriptase inhibitor, the nevirapine, accumulated at lower levels [18].
• Accumulation of lopinavir resistance-associated mutations over 3 years follow-up of patients on highly active antiretroviral therapy: implication in salvage therapy [31].
• Intra-individual variability in lopinavir plasma trough concentrations supports therapeutic drug monitoring [32].

References