Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients

AIDS ◽  
2006 ◽  
Vol 20 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Samir Vora ◽  
Anne-Geneviève Marcelin ◽  
Huldrych F Günthard ◽  
Philippe Flandre ◽  
Hans H Hirsch ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Clinical Validation ◽  
Genotypic Resistance ◽  
Resistance Score

scholarly journals Clinically Relevant Interpretation of Genotype and Relationship to Plasma Drug Concentrations for Resistance to Saquinavir-Ritonavir in Human Immunodeficiency Virus Type 1 Protease Inhibitor-Experienced Patients

2004 ◽  
Vol 48 (12) ◽  
pp. 4687-4692 ◽  
Author(s):  
Anne-Geneviève Marcelin ◽  
Cécile Dalban ◽  
Gilles Peytavin ◽  
Claire Lamotte ◽  
Rachid Agher ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Virological Response ◽  
Resistance Index ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Minimum Concentration ◽  
Drug Concentrations ◽  
Immunodeficiency Virus ◽  
Resistance Score

ABSTRACT It has been shown that virological protease inhibitor (PI) resistance mutations present at the initiation of saquinavir (SQV) plus ritonavir (RTV) therapy in PI-experienced patients are the strongest predictors of virological response. But most of the current resistance algorithms are adapted for unboosted SQV regimens. We applied a stepwise methodology for the development and validation of a clinically relevant genotypic resistance score for an SQV (800 mg twice per day [b.i.d.]) plus RTV (100 mg b.i.d.)-containing regimen. PI-experienced patients treated by this regimen achieved a human immunodeficiency virus plasma viral load (VL) of <200 copies/ml at months 3 to 5 for 41.7% of subjects. Adjusted in a multivariate analysis, taking into account all the confounding factors, such as the nucleoside used, five mutations were combined in a resistance score associated with a reduced virological response to an SQV-plus-RTV regimen: L24I, I62V, V82A/F/T/S, I84V, and L90IM. Patients with isolates harboring 0 to 1 mutation among the score achieved −2.20 log10 and −1.23 log10 copies/ml of VL reduction, respectively, while it was −0.27 log10 copies/ml for those with at least two mutations, classifying the isolates as “no evidence of resistance” (0 or 1 mutation) or “resistance ” (≥2 mutations). The minimum concentration in plasma (C min) of SQV alone was not associated with the virological response. However, the combination of the SQV C min and the genotypic score, expressed as the genotypic inhibitory quotient, was predictive of the virological response, suggesting that the interpretation of SQV concentrations in plasma should be done only in the context of the resistance index provided by viral genotype for PI-experienced patients.

scholarly journals Genotypic Resistance Analysis of the Virological Response to Fosamprenavir-Ritonavir in Protease Inhibitor-Experienced Patients in CONTEXT and TRIAD Clinical Trials

2008 ◽  
Vol 52 (12) ◽  
pp. 4251-4257 ◽  
Author(s):  
Anne-Geneviève Marcelin ◽  
Philippe Flandre ◽  
Jean-Michel Molina ◽  
Christine Katlama ◽  
Patrick Yeni ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Protease Inhibitor ◽  
Virological Response ◽  
Hiv Protease ◽  
Genotypic Resistance ◽  
Data Set ◽  
Hiv Rna ◽  
Step Procedure ◽  
Resistance Score ◽  
The Impact

ABSTRACT The aim of this study was to identify human immunodeficiency virus (HIV) protease mutations associated with virological response (VR) to fosamprenavir-ritonavir (FPV/r) in 113 protease inhibitor (PI)-experienced patients randomized in both CONTEXT and TRIAD clinical trials and receiving the same dose (700/100 mg twice daily) of FPV/r. The impact of each protease mutation on the VR to FPV/r, defined as the decrease in HIV RNA at week 12, was investigated with nonparametric analyses. A step-by-step procedure was done using a Jonckheere-Terpstra (JT) test that retains the group of mutations most strongly associated with the VR. Mutations at the following 14 codons were associated with a reduced VR to FPV/r: 10, 15, 33, 46, 54, 60, 62, 63, 72, 73, 82, 84, 89, and 90. The JT procedure led to selecting the CONTEXT/TRIAD genotypic set of mutations, I15V, M46I/L, I54L/M/V, D60E, L63P/T, and I84V, as providing the strongest association with the VR (P = 1.45 × 10−11). In the nine patients with zero mutations within this set, the median decrease in HIV RNA was −2.63 log copies/ml, and was −2.22 (n = 45), −1.50 (n = 26), −0.58 (n = 23), −0.47 (n = 6), −0.13 (n = 3), and 0.04 (n = 1) log copies/ml in those with one, two, three, four, five, and six mutations, respectively. This study identified six mutations associated with VR to FPV/r. Some of these mutations are shared with the current FPV/r Agence Nationale de Recherches sur le SIDA (ANRS) resistance score, which has been cross-validated in the CONTEXT/TRIAD data set, suggesting that the current ANRS FPV/r score is a useful tool for the prediction of VR to FPV/r in PI-experienced patients.

scholarly journals Tipranavir-Ritonavir Genotypic Resistance Score in Protease Inhibitor-Experienced Patients

2008 ◽  
Vol 52 (9) ◽  
pp. 3237-3243 ◽  
Author(s):  
Anne-Genevieve Marcelin ◽  
Bernard Masquelier ◽  
Diane Descamps ◽  
Jacques Izopet ◽  
Charlotte Charpentier ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Strong Association ◽  
Single Variable ◽  
Phenotypic Analysis ◽  
Genotypic Resistance ◽  
Hiv Rna ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Previously Treated ◽  
Resistance Score

ABSTRACT To identify mutations associated with the virological response (VR) to a tipranavir-ritonavir (TPV/r)-based regimen, 143 patients previously treated with protease inhibitor (PI) were studied. VR was defined by a decrease of at least 1 log10 in, or undetectable, human immunodeficiency virus (HIV) RNA at month 3. The effect of each mutation in the protease, considering all variants at a residue as a single variable, on the VR to TPV/r was investigated. Mutations at six residues were associated with a lower VR (E35D/G/K/N, M36I/L/V, Q58E, Q61D/E/G/H/N/R, H69I/K/N/Q/R/Y, and L89I/M/R/T/V), and one mutation was associated with a higher VR (F53L/W/Y). The genotypic score M36I/L/V − F53L/W/Y + Q58E + H69I/K/N/Q/R/Y + L89I/M/R/T/V was selected as providing a strong association with VR. For the seven patients with a genotypic score of −1 (viruses with only mutation at codon 53), the percentage of responders was 100% and the percentages were 79%, 56%, 33%, 21%, and 0% for those with scores of 0, 1, 2, 3, and 4, respectively. The percentage of patients showing a response to TPV/r was lower for patients infected with non-clade B viruses (n = 16, all non-B subtypes considered together) than for those infected with clade B viruses (n = 127) (25% and 59%, respectively; P = 0.015). Most mutations associated with VR to TPV/r had not previously been associated with PI resistance. This is consistent with phenotypic analysis showing that TPV has a unique resistance profile. Mutations at five positions (35, 36, 61, 69, and 89) were observed significantly more frequently in patients infected with a non-B subtype than in those infected with the B subtype, probably explaining the lower VR observed in these patients.

scholarly journals Predictive Genotypic Algorithm for Virologic Response to Lopinavir-Ritonavir in Protease Inhibitor-Experienced Patients

2007 ◽  
Vol 51 (9) ◽  
pp. 3067-3074 ◽  
Author(s):  
Martin S. King ◽  
Richard Rode ◽  
Isabelle Cohen-Codar ◽  
Vincent Calvez ◽  
Anne-Geneviève Marcelin ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Optimal Algorithm ◽  
Virologic Response ◽  
Hiv Protease ◽  
Genotypic Resistance ◽  
Phenotypic Resistance ◽  
Response Data ◽  
Mutation Score ◽  
Antiviral Activities ◽  
Multivariable Analyses

ABSTRACT Several genotypic resistance algorithms have been proposed for quantitation of the degree of phenotypic resistance to the human immunodeficiency virus (HIV) protease inhibitor (PI) lopinavir (LPV), including the original LPV mutation score. In this study, we retrospectively evaluated 21 codons in HIV protease known to be associated with PI resistance in a large antiretroviral agent-experienced observational patient cohort, “Autorisation Temporaire d'Utilization” (ATU), to assess whether a more optimal algorithm could be derived by using virologic response data from patients treated with LPV in combination with ritonavir (LPV/r). Five of the 11 mutations constituting the LPV mutation score were not associated with a virologic response, while 4 additional mutations not included in this score demonstrated an association. Therefore, the LPV ATU score, which includes mutations at codons 10, 20, 24, 33, 36, 47, 48, 54, 82, and 84, was constructed and shown in two different types of multivariable analyses of the ATU cohort to be a better predictor of the virologic response than the LPV mutation score. The LPV ATU score was also more strongly associated with a virologic response when it was applied to independent clinical trial populations of PI-experienced patients receiving LPV/r. This study provides the basis for a new genotypic resistance algorithm that is useful for predicting the antiviral activities of LPV/r-based regimens in PI-experienced patients. The refined algorithm may be useful in making clinical treatment decisions and in refining genetic and pharmacologic methods for assessing the activity of LPV/r.

scholarly journals Clinical Validation and Applicability of Different Tipranavir/Ritonavir Genotypic Scores in HIV-1 Protease Inhibitor-Experienced Patients

2009 ◽  
Vol 7 (4) ◽  
pp. 425-433 ◽  
Author(s):  
Annalisa Saracino ◽  
Laura Monno ◽  
Alessandra Tartaglia ◽  
Carmine Tinelli ◽  
Elena Seminari ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Clinical Validation ◽  
Hiv 1

Two Different Patterns of Mutations are Involved in the Genotypic Resistance Score for Atazanavir Boosted Versus Unboosted by Ritonavir in Multiple Failing Patients

Infection ◽  
2009 ◽  
Vol 37 (3) ◽  
pp. 233-243 ◽  
Author(s):  
M. M. Santoro ◽  
◽  
A. Bertoli ◽  
P. Lorenzini ◽  
F. Ceccherini-Silberstein ◽  
...  
Keyword(s):  
Genotypic Resistance ◽  
Resistance Score

Impact of Adding Enfuvirtide to the Predictive Value of the Darunavir Genotypic Resistance Score

2011 ◽  
Vol 57 (1) ◽  
pp. e15-e17
Author(s):  
Charlotte Charpentier ◽  
Sidonie Lambert-Niclot ◽  
Lucile Larrouy ◽  
Gilles Peytavin ◽  
Marc-Antoine Valantin ◽  
...  
Keyword(s):  
Predictive Value ◽  
Genotypic Resistance ◽  
Resistance Score

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

2005 ◽  
Vol 49 (5) ◽  
pp. 1720-1726 ◽  
Author(s):  
Anne-Geneviève Marcelin ◽  
Isabelle Cohen-Codar ◽  
Martin S. King ◽  
Philippe Colson ◽  
Emmanuel Guillevic ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Drug Exposure ◽  
Virologic Response ◽  
Therapeutic Drug ◽  
Resistance Mutations ◽  
Genotypic Resistance ◽  
Hiv Rna ◽  
Inhibitor Resistance ◽  
Hiv 1

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 log10 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.

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