Phase I and II Study of the Safety, Virologic Effect, and Pharmacokinetics/Pharmacodynamics of Single-Dose 3-O-(3′,3′-Dimethylsuccinyl)Betulinic Acid (Bevirimat) against Human Immunodeficiency Virus Infection

ABSTRACT Bevirimat [3-O-(3′,3′-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-human immunodeficiency virus (HIV) drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Four cohorts of six HIV-infected adults, with CD4 counts of >200 and plasma viral loads of 5,000 to 250,000 transcripts/ml and not currently receiving antiretroviral therapy, were randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat. Thirty blood samples for drug concentrations and 20 HIV RNA measures were collected from each subject over a 20-day period. Candidate pharmacokinetic/pharmacodynamic models were fit to individual subjects by maximum likelihood followed by Bayesian estimation; model discrimination was by corrected Akaike's Information Criterion. The bevirimat pharmacokinetics was well described by an oral two-compartment linear model (r 2, 0.98), with a mean (percent coefficient of variation) half-life of 60.3 (13.6) h and apparent oral clearance of bevirimat from the plasma compartment of 0.17 (18) liters/h. HIV RNA was modeled as being produced in infected CD4 cells, with bevirimat inhibiting infection of new CD4 cells thru a Hill-type function (r 2, 0.87). Single oral doses of bevirimat were well tolerated and demonstrated a dose-dependent reduction in viral load. The average maximum reduction from baseline following the 150- and 250-mg doses was greater than 0.45 log10, with individual patients having reductions of greater than 0.7 log10. No bevirimat resistance mutations were detected during the course of the study.

Download Full-text

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

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.12.4687-4692.2004 ◽

2004 ◽

Vol 48 (12) ◽

pp. 4687-4692 ◽

Cited By ~ 37

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.

Download Full-text

Discrepancies between Protease Inhibitor Concentrations and Viral Load in Reservoirs and Sanctuary Sites in Human Immunodeficiency Virus-Infected Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.1.238-243.2003 ◽

2003 ◽

Vol 47 (1) ◽

pp. 238-243 ◽

Cited By ~ 125

Author(s):

Caroline Solas ◽

Alain Lafeuillade ◽

Philippe Halfon ◽

Stéphane Chadapaud ◽

Gilles Hittinger ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Lymph Node ◽

Viral Load ◽

Lymphoid Tissue ◽

Drug Penetration ◽

Hiv Rna ◽

Drug Concentrations ◽

Immunodeficiency Virus ◽

Rna Levels

ABSTRACT The variable penetration of antiretroviral drugs into sanctuary sites may contribute to the differential evolution of human immunodeficiency virus (HIV) and the emergence of drug resistance. We evaluated the penetration of indinavir, nelfinavir, and lopinavir-ritonavir (lopinavir/r) in the central nervous system, genital tract, and lymphoid tissue and assessed the correlation with residual viral replication. Plasma, cerebrospinal fluid (CSF), semen, and lymph node biopsy samples were collected from 41 HIV-infected patients on stable highly active antiretroviral therapy regimens to determine drug concentrations and HIV RNA levels. When HIV RNA was detectable, sequencing of the reverse transcriptase and protease genes was performed. Ratios of the concentration in semen/concentration in plasma were 1.9 for indinavir, 0.08 for nelfinavir, and 0.07 for lopinavir. Only indinavir was detectable in CSF, with a concentration in CSF/concentration in plasma ratio of 0.17. Differential penetration into lymphoid tissue was observed, with concentration in lymph node tissue/concentration in plasma ratios of 2.07, 0.58, and 0.21 for indinavir, nelfinavir, and lopinavir, respectively. HIV RNA levels were <50 copies/ml in all CSF samples of patients in whom HIV RNA was not detectable in plasma. HIV RNA was detectable in the semen of three patients (two patients receiving nelfinavir and one patient receiving lopinavir/r), and its detection was associated with multiple resistance mutations, while the viral load in plasma was undetectable. HIV RNA was detectable in all lymph node tissue samples. Differential drug penetration was observed among the three protease inhibitors in the sanctuary sites, but there was no correlation between drug levels and HIV RNA levels, suggesting that multiple factors are involved in the persistence of viral reservoirs. Further studies are required to clarify the role and clinical relevance of drug penetration in sanctuaries in terms of long-term efficacy and drug resistance.

Download Full-text

Retracing the Evolutionary Pathways of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors: Virus Fitness in the Absence and in the Presence of Drug

Journal of Virology ◽

10.1128/jvi.74.18.8524-8531.2000 ◽

2000 ◽

Vol 74 (18) ◽

pp. 8524-8531 ◽

Cited By ~ 130

Author(s):

Fabrizio Mammano ◽

Virginie Trouplin ◽

Veronique Zennou ◽

Francois Clavel

Keyword(s):

Human Immunodeficiency Virus ◽

Protease Inhibitors ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Drug Concentration ◽

Resistance Mutations ◽

Drug Concentrations ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) resistance to protease inhibitors (PI) is a major obstacle to the full success of combined antiretroviral therapy. High-level resistance to these compounds is the consequence of stepwise accumulation of amino acid substitutions in the HIV-1 protease (PR), following pathways that usually differ from one inhibitor to another. The selective advantage conferred by resistance mutations may depend upon several parameters: the impact of the mutation on virus infectivity in the presence or absence of drug, the nature of the drug, and its local concentration. Because drug concentrations in vivo are subject to extensive variation over time and display a markedly uneven tissue distribution, the parameters of selection for HIV-1 resistance to PI in treated patients are complex and poorly understood. In this study, we have reconstructed a large series of HIV-1 mutants that carry single or combined mutations in the PR, retracing the accumulation pathways observed in ritonavir-, indinavir-, and saquinavir-treated patients. We have then measured the phenotypic resistance and the drug-free infectivity of these mutant viruses. A deeper insight into the evolutionary value of HIV-1 PR mutants came from a novel assay system designed to measure the replicative advantage of mutant viruses as a function of drug concentration. By tracing the resultant fitness profiles, we determined the range of drug concentrations for which mutant viruses displayed a replicative advantage over the wild type and the extent of this advantage. Fitness profiles were fully consistent with the order of accumulation of resistance mutations observed in treated patients and further emphasise the key importance of local drug concentration in the patterns of selection of drug-resistant HIV-1 mutants.

Download Full-text

Recovery and Analysis of Human Immunodeficiency Virus Type 1 (HIV) RNA Sequences from Plasma Samples with Low HIV RNA Levels

Journal of Clinical Microbiology ◽

10.1128/jcm.38.1.309-312.2000 ◽

2000 ◽

Vol 38 (1) ◽

pp. 309-312

Author(s):

Jordi Niubò ◽

Wuyi Li ◽

Keith Henry ◽

Alejo Erice

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Rna Extraction ◽

Plasma Samples ◽

Resistance Mutations ◽

Hiv Rna ◽

Immunodeficiency Virus ◽

Rna Levels

ABSTRACT Amplification of human immunodeficiency virus type 1 (HIV) reverse transcriptase (RT) and protease (PT) sequences from plasma is difficult when HIV RNA levels are low, and it usually cannot be accomplished in samples with <1,000 HIV RNA copies/ml. Because the RNA extraction step is critical for the success of subsequent amplifications and sequence analyses, two RNA extraction methods were compared to study plasma samples with low HIV RNA levels. Forty-four plasma samples containing <500 HIV RNA copies/ml in a branched-DNA (bDNA) assay (Quantiplex HIV RNA assay version 2.0 [Chiron Corp., Emeryville, Calif.]) were studied. RNA was extracted by using two commercial kits (QIAamp Viral RNA kit [Qiagen, Hilden, Germany] and NucliSens kit [Organon Teknika, Boxtel, The Netherlands]). Fragments (1,144 bp) encompassing HIV PT and RT sequences were amplified by nested PCRs. Amplified products were sequenced by using a commercial kit (Applied Biosystems). HIV RNA was recovered from a total of 21 plasma samples, including 20 samples after extraction by the NucliSens method, and 8 samples after extraction by the QIAamp method ( P < 0.05). Mean HIV RNA levels in these samples, measured by an ultrasensitive bDNA assay (Quantiplex HIV RNA assay version 3.0; Chiron Corp., Emeryville, Calif.), were 848 copies/ml (median, 666; range, 154 to 2,606 copies/ml). Analysis of RT and PT sequences in five samples demonstrated an average of 3.8 and 2.4 resistance mutations in these regions, respectively. The NucliSens RNA extraction kit is a valuable method for obtaining HIV RNA for genotypic studies from plasma fractions of individuals with low HIV RNA levels.

Download Full-text

Interactions Between Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase

Journal of General Virology ◽

10.1099/0022-1317-75-5-951 ◽

1994 ◽

Vol 75 (5) ◽

pp. 951-957 ◽

Cited By ~ 99

Author(s):

B. A. Larder

Keyword(s):

Human Immunodeficiency Virus ◽

Drug Resistance ◽

Reverse Transcriptase ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Resistance Mutations ◽

Drug Resistance Mutations ◽

Immunodeficiency Virus

Download Full-text

The Fitness Cost of Mutations Associated with Human Immunodeficiency Virus Type 1 Drug Resistance Is Modulated by Mutational Interactions

Journal of Virology ◽

10.1128/jvi.02712-06 ◽

2006 ◽

Vol 81 (6) ◽

pp. 3037-3041 ◽

Cited By ~ 93

Author(s):

Mian-er Cong ◽

Walid Heneine ◽

J. Gerardo García-Lerma

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Fitness Cost ◽

Resistance Mutations ◽

Drug Pressure ◽

Critical Determinant ◽

Immunodeficiency Virus ◽

Cost Of Resistance

ABSTRACT It is generally accepted that the fitness cost of resistance mutations plays a role in the persistence of transmitted drug-resistant human immunodeficiency virus type 1 and that mutations that confer a high fitness cost are less able to persist in the absence of drug pressure. Here, we show that the fitness cost of reverse transcriptase (RT) mutations can vary within a 72-fold range. We also demonstrate that the fitness cost of M184V and K70R can be decreased or enhanced by other resistance mutations such as D67N and K219Q. We conclude that the persistence of transmitted RT mutants might range widely on the basis of fitness and that the modulation of fitness cost by mutational interactions will be a critical determinant of persistence.

Download Full-text