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 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 Gag Mutations Can Impact Virological Response to Dual-Boosted Protease Inhibitor Combinations in Antiretroviral-Naïve HIV-Infected Patients

2010 ◽  
Vol 54 (7) ◽  
pp. 2910-2919 ◽  
Author(s):  
Lucile Larrouy ◽  
C. Chazallon ◽  
R. Landman ◽  
C. Capitant ◽  
G. Peytavin ◽  
...  
Keyword(s):  
Protease Inhibitor ◽  
Virological Response ◽  
Cleavage Site ◽  
Pilot Trial ◽  
Baseline Viral Load ◽  
Coding Region ◽  
Site Mutation ◽  
Hiv Rna ◽  
The Impact

ABSTRACT ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P = 0.04) and 449 (p1/p6 gag ) (P = 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6 pol ) was associated with virological response (P = 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

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.

Mathematical Modeling of the Interrelationship of CD4 Lymphocyte Count and Viral Load Changes Induced by the Protease Inhibitor Indinavir

1998 ◽  
Vol 42 (2) ◽  
pp. 358-361 ◽  
Author(s):  
George L. Drusano ◽  
Daniel S. Stein
Keyword(s):  
Viral Load ◽  
Protease Inhibitor ◽  
Disease Progression ◽  
Antiviral Effect ◽  
Hiv Protease ◽  
Cd4 Cells ◽  
Viral Inhibition ◽  
Hiv Rna ◽  
Cell Counts ◽  
Cd4 Cell

ABSTRACT While CD4 cell counts are widely used to predict disease progression in human immunodeficiency virus (HIV)-infected patients, they are poorly explanatory of the progression to AIDS or death after the introduction of chemotherapy. Changes in HIV load (as measured by RNA PCR) have been shown to be a much better predictor of the risk of disease progression. Since the interrelationship of these markers is of great clinical interest, we modeled the time-averaged return of CD4 cell count and change in viral load subsequent to therapy with the HIV protease inhibitor indinavir. We found that CD4 cell return was significantly related to both the baseline CD4 count (r 2 = 0.86, P < 0.001) and the decline in HIV RNA PCR-determined viral load (also referred to in this work as the HIV RNA PCR decline) (r 2 = 0.60, P < 0.01). Simultaneously modeling both influences in a linked nonlinear model (r 2 = 0.93, P < 0.001) demonstrated that (i) the starting number of CD4 cells accounted for the majority of the change in CD4 cell return and (ii) the return of CD4 cells attributable to viral load decrease was 50% of maximal with only a decrease of approximately 0.2 log of HIV RNA as modeled from the first 12 weeks of therapy. Much greater viral inhibition beyond that necessary for maximal CD4 cell return is possible. Given that HIV RNA PCR decline is more strongly linked to ultimate clinical course in HIV disease, our findings indicate that CD4 return is potentially misleading as an indicator of antiviral effect, since it is determined more by the starting CD4 value than by viral load decline and since near-maximal changes occur with minimal antiviral effect.

scholarly journals Overcoming challenges to data quality in the ASPREE clinical trial

Trials ◽  
2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Jessica E. Lockery ◽  
◽  
Taya A. Collyer ◽  
Christopher M. Reid ◽  
Michael E. Ernst ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Missing Data ◽  
Data Quality ◽  
Large Scale ◽  
Controlled Trial ◽  
Data Entry ◽  
Quality Data ◽  
Community Based ◽  
Data Set ◽  
The Impact

Abstract Background Large-scale studies risk generating inaccurate and missing data due to the complexity of data collection. Technology has the potential to improve data quality by providing operational support to data collectors. However, this potential is under-explored in community-based trials. The Aspirin in reducing events in the elderly (ASPREE) trial developed a data suite that was specifically designed to support data collectors: the ASPREE Web Accessible Relational Database (AWARD). This paper describes AWARD and the impact of system design on data quality. Methods AWARD’s operational requirements, conceptual design, key challenges and design solutions for data quality are presented. Impact of design features is assessed through comparison of baseline data collected prior to implementation of key functionality (n = 1000) with data collected post implementation (n = 18,114). Overall data quality is assessed according to data category. Results At baseline, implementation of user-driven functionality reduced staff error (from 0.3% to 0.01%), out-of-range data entry (from 0.14% to 0.04%) and protocol deviations (from 0.4% to 0.08%). In the longitudinal data set, which contained more than 39 million data values collected within AWARD, 96.6% of data values were entered within specified query range or found to be accurate upon querying. The remaining data were missing (3.4%). Participant non-attendance at scheduled study activity was the most common cause of missing data. Costs associated with cleaning data in ASPREE were lower than expected compared with reports from other trials. Conclusions Clinical trials undertake complex operational activity in order to collect data, but technology rarely provides sufficient support. We find the AWARD suite provides proof of principle that designing technology to support data collectors can mitigate known causes of poor data quality and produce higher-quality data. Health information technology (IT) products that support the conduct of scheduled activity in addition to traditional data entry will enhance community-based clinical trials. A standardised framework for reporting data quality would aid comparisons across clinical trials. Trial registration International Standard Randomized Controlled Trial Number Register, ISRCTN83772183. Registered on 3 March 2005.

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 Relationship between Measures of HIV Reactivation and Decline of the Latent Reservoir under Latency-Reversing Agents

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
Janka Petravic ◽  
Thomas A. Rasmussen ◽  
Sharon R. Lewin ◽  
Stephen J. Kent ◽  
Miles P. Davenport
Keyword(s):  
Clinical Trials ◽  
Life Span ◽  
Substantial Reduction ◽  
Latent Reservoir ◽  
Hiv Rna ◽  
Hiv Transcription ◽  
Latently Infected ◽  
Infected Cells ◽  
The Impact ◽  
Reversing Agents

ABSTRACT Antiretroviral-free HIV remission requires substantial reduction of the number of latently infected cells and enhanced immune control of viremia. Latency-reversing agents (LRAs) aim to eliminate latently infected cells by increasing the rate of reactivation of HIV transcription, which exposes these cells to killing by the immune system. As LRAs are explored in clinical trials, it becomes increasingly important to assess the effect of an increased HIV reactivation rate on the decline of latently infected cells and to estimate LRA efficacy in increasing virus reactivation. However, whether the extent of HIV reactivation is a good predictor of the rate of decline of the number of latently infected cells is dependent on a number of factors. Our modeling shows that the mechanisms of maintenance and clearance of the reservoir, the life span of cells with reactivated HIV, and other factors may significantly impact the relationship between measures of HIV reactivation and the decline in the number of latently infected cells. The usual measures of HIV reactivation are the increase in cell-associated HIV RNA (CA RNA) and/or plasma HIV RNA soon after administration. We analyze two recent studies where CA RNA was used to estimate the impact of two novel LRAs, panobinostat and romidepsin. Both drugs increased the CA RNA level 3- to 4-fold in clinical trials. However, cells with panobinostat-reactivated HIV appeared long-lived (half-life > 1 month), suggesting that the HIV reactivation rate increased by approximately 8%. With romidepsin, the life span of cells that reactivated HIV was short (2 days), suggesting that the HIV reactivation rate may have doubled under treatment. IMPORTANCE Long-lived latently infected cells that persist on antiretroviral treatment (ART) are thought to be the source of viral rebound soon after ART interruption. The elimination of latently infected cells is an important step in achieving antiretroviral-free HIV remission. Latency-reversing agents (LRAs) aim to activate HIV expression in latently infected cells, which could lead to their death. Here, we discuss the possible impact of the LRAs on the reduction of the number of latently infected cells, depending on the mechanisms of their loss and self-renewal and on the life span of the cells that have HIV transcription activated by the LRAs.

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.

Sign in / Sign up

Export Citation Format

Share Document