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 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.

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 Amprenavir Inhibitory Quotient and Virological Response in Human Immunodeficiency Virus-Infected Patients on an Amprenavir-Containing Salvage Regimen without or with Ritonavir

2002 ◽  
Vol 46 (2) ◽  
pp. 570-574 ◽  
Author(s):  
Xavier Duval ◽  
Claire Lamotte ◽  
Ester Race ◽  
Diane Descamps ◽  
Florence Damond ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Virological Response ◽  
Protease Inhibitor Therapy ◽  
Salvage Regimen ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Group A ◽  
The Mean ◽  
Group B

ABSTRACT The efficacy of an amprenavir (APV)-containing therapy without (group A) or with (group B) ritonavir was assessed in patients with failure of previous protease inhibitor therapy for human immunodeficiency virus (HIV) infection. The mean minimal plasma APV concentrations in groups A and B were 58 and 1,320 ng/ml, respectively, corresponding to APV inhibitory quotients of 0.2 (range, 0.03 to 0.70) and 7.0 (range, 1.4 to 145), respectively. At week 24, 2 of 8 and 13 of 14 patients in groups A and B, respectively, had <200 HIV RNA copies/ml of plasma, including 4 of 5 patients infected with APV-resistant viruses.

scholarly journals In Vitro Resistance Profile of the Human Immunodeficiency Virus Type 1 Protease Inhibitor BMS-232632

2000 ◽  
Vol 44 (9) ◽  
pp. 2319-2326 ◽  
Author(s):  
Yi-Fei Gong ◽  
Brett S. Robinson ◽  
Ronald E. Rose ◽  
Carol Deminie ◽  
Timothy P. Spicer ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Protease Inhibitors ◽  
Selection Process ◽  
Cross Resistance ◽  
Phenotypic Analysis ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT BMS-232632 is an azapeptide human immunodeficiency virus (HIV) type 1 (HIV-1) protease inhibitor that displays potent anti-HIV-1 activity (50% effective concentration [EC50], 2.6 to 5.3 nM; EC90, 9 to 15 nM). In vitro passage of HIV-1 RF in the presence of inhibitors showed that BMS-232632 selected for resistant variants more slowly than nelfinavir or ritonavir did. Genotypic and phenotypic analysis of three different HIV strains resistant to BMS-232632 indicated that an N88S substitution in the viral protease appeared first during the selection process in two of the three strains. An I84V change appeared to be an important substitution in the third strain used. Mutations were also observed at the protease cleavage sites following drug selection. The evolution to resistance seemed distinct for each of the three strains used, suggesting multiple pathways to resistance and the importance of the viral genetic background. A cross-resistance study involving five other protease inhibitors indicated that BMS-232632-resistant virus remained sensitive to saquinavir, while it showed various levels (0.1- to 71-fold decrease in sensitivity)-of cross-resistance to nelfinavir, indinavir, ritonavir, and amprenavir. In reciprocal experiments, the BMS-232632 susceptibility of HIV-1 variants selected in the presence of each of the other HIV-1 protease inhibitors showed that the nelfinavir-, saquinavir-, and amprenavir-resistant strains of HIV-1 remained sensitive to BMS-232632, while indinavir- and ritonavir-resistant viruses displayed six- to ninefold changes in BMS-232632 sensitivity. Taken together, our data suggest that BMS-232632 may be a valuable protease inhibitor for use in combination therapy.

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.

scholarly journals Variant Human Immunodeficiency Virus Type 1 Proteases and Response to Combination Therapy Including a Protease Inhibitor

2001 ◽  
Vol 45 (3) ◽  
pp. 893-900 ◽  
Author(s):  
Jean Servais ◽  
Christine Lambert ◽  
Elodie Fontaine ◽  
Jean-Marc Plesséria ◽  
Isabelle Robert ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Drug Regimen ◽  
Reference Sequence ◽  
Wild Type Virus ◽  
Protease Gene ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The objective of this observational study was to assess the genetic variability in the human immunodeficiency virus (HIV) protease gene from HIV type 1 (HIV-1)-positive (clade B), protease inhibitor-naı̈ve patients and to evaluate its association with the subsequent effectiveness of a protease inhibitor-containing triple-drug regimen. The protease gene was sequenced from plasma-derived virus from 116 protease inhibitor-naı̈ve patients. The virological response to a triple-drug regimen containing indinavir, ritonavir, or saquinavir was evaluated every 3 months for as long as 2 years (n = 40). A total of 36 different amino acid substitutions compared to the reference sequence (HIV-1 HXB2) were detected. No substitutions at the active site similar to the primary resistance mutations were found. The most frequent substitutions (prevalence, >10%) at baseline were located at codons 15, 13, 12, 62, 36, 64, 41, 35, 3, 93, 77, 63, and 37 (in ascending order of frequency). The mean number of polymorphisms was 4.2. A relatively poorer response to therapy was associated with a high number of baseline polymorphisms and, to a lesser extent, with the presence of I93L at baseline in comparison with the wild-type virus. A71V/T was slightly associated with a poorer response to first-line ritonavir-based therapy. In summary, within clade B viruses, protease gene natural polymorphisms are common. There is evidence suggesting that treatment response is associated with this genetic background, but most of the specific contributors could not be firmly identified. I93L, occurring in about 30% of untreated patients, may play a role, as A71V/T possibly does in ritonavir-treated patients.

scholarly journals Determinants of Viral Resuppression or Persistent Virologic Failure After Initial Failure With Second-Line Antiretroviral Treatment Among Asian Children and Adolescents With HIV

2019 ◽  
Vol 9 (2) ◽  
pp. 253-256
Author(s):  
Sirinya Teeraananchai ◽  
Stephen J Kerr ◽  
Monica Gandhi ◽  
Viet Chau Do ◽  
Lam Van Nguyen ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Antiretroviral Treatment ◽  
Virologic Failure ◽  
Second Line ◽  
Hiv Rna ◽  
Immunodeficiency Virus ◽  
Asian Children ◽  
Perinatally Acquired

Abstract Of 56 children with perinatally acquired human immunodeficiency virus (HIV) who had been prescribed second-line protease inhibitor–based antiretroviral therapy and had ≥1 previous episode of viral failure (HIV RNA, ≥1000 copies/mL), 46% had ≥1, 34% had ≥2, and 23% had ≥3 consecutive episodes of viral failure during the 2 years of follow-up. Two of these children experienced a major protease inhibitor mutation.

scholarly journals Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1

2013 ◽  
Vol 57 (9) ◽  
pp. 4290-4299 ◽  
Author(s):  
Vici Varghese ◽  
Yumi Mitsuya ◽  
W. Jeffrey Fessel ◽  
Tommy F. Liu ◽  
George L. Melikian ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protease Inhibitor ◽  
Cross Resistance ◽  
Amino Acid Substitutions ◽  
Phenotypic Properties ◽  
The Public ◽  
Immunodeficiency Virus ◽  
The Many ◽  
High Level ◽  
Infectious Molecular Clones

ABSTRACTThe many genetic manifestations of HIV-1 protease inhibitor (PI) resistance present challenges to research into the mechanisms of PI resistance and the assessment of new PIs. To address these challenges, we created a panel of recombinant multi-PI-resistant infectious molecular clones designed to represent the spectrum of clinically relevant multi-PI-resistant viruses. To assess the representativeness of this panel, we examined the sequences of the panel's viruses in the context of a correlation network of PI resistance amino acid substitutions in sequences from more than 10,000 patients. The panel of recombinant infectious molecular clones comprised 29 of 41 study-defined PI resistance amino acid substitutions and 23 of the 27 tightest amino acid substitution clusters. Based on their phenotypic properties, the clones were classified into four groups with increasing cross-resistance to the PIs most commonly used for salvage therapy: lopinavir (LPV), tipranavir (TPV), and darunavir (DRV). The panel of recombinant infectious molecular clones has been made available without restriction through the NIH AIDS Research and Reference Reagent Program. The public availability of the panel makes it possible to compare the inhibitory activities of different PIs with one another. The diversity of the panel and the high-level PI resistance of its clones suggest that investigational PIs active against the clones in this panel will retain antiviral activity against most if not all clinically relevant PI-resistant viruses.

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