Predictors of Virological Response to Atazanavir in Protease Inhibitor-Experienced Patients

Barrios, Ana; Rendón, Ana; Gallego, Óscar; Martín-Carbonero, Luz; Valer, Luisa; Ríos, Pilar; Maida, Ivana; García-Benayas, Teresa; Jiménez-Nácher, Inmaculada; González-Lahoz, Juan; Soriano, Vincent

doi:10.1310/3hl3-hhbd-wklr-xell

Cited by 57 publications

(37 citation statements)

References 12 publications

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“…About 20%-50% of patients exposed to ATV may develop hyperbilirubinemia that can be severe in about 6% of cases [57]. Several studies have shown the correlation between ATV plasma levels and the risk of bilirubin elevations [47,48,58]. Polymorphisms at the UGT1A1 gene have been related with a diminished activity of the enzyme, affecting the metabolism of bilirubin.…”

Section: Pharmacogenetics Of Atazanavirmentioning

confidence: 99%

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Barc¹

2013

J Pharmacogenom Pharmacoproteomics

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Section: Pharmacogenetics Of Atazanavirmentioning

confidence: 99%

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Barc¹

2013

J Pharmacogenom Pharmacoproteomics

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“…2 In addition, data from PI-experienced patients revealed that the median number of PI-associated resistance mutations was lower in patients showing virological response than in non-responders. 9 As with other PIs, failure of ATV is often rather better explained by lack of potency than by the acquisition of primary resistance mutations, especially in patients without previous PI failure. 10 In PI-experienced patients, the genotypic inhibitory quotient (GIQ) has been proven to be a good predictor of virological response to ATV, as it integrates both resistance mutations and drug plasma exposure.…”

Section: Drug Resistancementioning

confidence: 99%

“…10 In PI-experienced patients, the genotypic inhibitory quotient (GIQ) has been proven to be a good predictor of virological response to ATV, as it integrates both resistance mutations and drug plasma exposure. 9 …”

Section: Drug Resistancementioning

confidence: 99%

Role of atazanavir in the treatment of HIV infection

Soriano¹

2008

TCRM

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Atazanavir (ATV) is one of the latest protease inhibitors (PI) approved for the treatment of HIV infection. The drug has a relatively long-life (∼7 h) and large inhibitory quotient which allows once daily administration. It is generally well tolerated and the main side effect is hyperbilirubinemia, since ATV inhibits the hepatic uridin-glucoronyl-transferase. A signature mutation at the protease gene, I50L, may confer loss of susceptibility to the drug. Interestingly, it produces hypersusceptibility to all other PIs. When ATV is pharmacokinetically boosted with ritonavir (r) 100 mg/day, a greater genetic barrier for resistance is achieved, and generally more than 3 major PI resistance associated mutations are needed to result in ATV resistance. In drugnaïve subjects, regimens based on ATV/r have shown non-inferiority compared to lopinavir (LPV)/r (CASTLE study) or fosamprenavir/r (ALERT trial), generally with improved tolerance (less diarrhea and dyslipidemia). Given its good tolerance and convenience, ATV has been proven to be successful as a simplifi cation strategy in switch studies (ie, SWAN and SLOAT) conducted in patients with complete virological suppression under other PI-based regimens. Finally, ATV/r-based combinations have shown to be equivalent in terms of viral response to other PI/r-containing regimens, including LPV/r, in rescue interventions in patients failing other PI regimens (ie, studies AI424-045 and NADIS).

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“…54 A direct corelation between ATV plasma concentrations and bilirubin levels has also been noticed by others. 55 Most PI are subject to P-gp transportation. Polymorphisms at the MDR1 gene that affect P-gp activity may be the genetic underlying mechanism for significant inter-individual variations in PI plasma levels.…”

Section: Protease Inhibitorsmentioning

confidence: 99%

“…These authors observed a reduction in virus production when P-gp was overexpressed at the surface of a continuous CD4 þ human T-leukemic cell line infected with HIV-1. 55 This reduction in viral infectivity occurred both during the fusion of viral and plasma membranes and at subsequent steps in the HIV-1 cycle. However, Ifergan et al 79 compared infected and non-infected Caucasian individuals highly exposed to HIV and they observed no differences in the distribution of P-gp genotypes between both groups, suggesting that P-gp expression does not play a major role in the susceptibility to HIV infection.…”

Section: Pharmacogenetics and Efficacy Of Antiretroviral Drugsmentioning

confidence: 99%

Overview of the pharmacogenetics of HIV therapy

Rodrı́guez-Nóvoa

Barreiro²,

Jiménez-Nácher

et al. 2006

Pharmacogenomics J

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The administration of standard doses of most antiretroviral drugs results in significant variations in plasma drug concentrations among different individuals, influencing antiviral activity as well as incidence of drug-related toxicities. The reasons for this large inter-individual variability in drug levels are multifactorial, and involve differences in metabolism related to gender, concomitant medications, drug compliance, underlying diseases and genetic factors. Pharmacogenetics is the discipline that analyses the genetic basis for the inter-individual variation in the body disposition of drugs. One of its main goals is to give grounds to individualized treatment. The majority of pharmacogenetic traits so far have involved drug metabolism. This is the case for the inherited variation in the pharmacokinetics and pharmacodynamics of drugs such as hydralazine or isoniazid, which is due to polymorphisms in the N-acetyltransferase-2 (NAT2) gene, which allows splitting the population into three categories: slow, intermediate, and fast metabolizers. Pharmacogenetic studies conducted so far with antiretroviral drugs have focussed on metabolizer enzymes at the liver and on transporter proteins on cell membranes. Herein, we review the most relevant metabolizer enzymes and protein transporters, along with the genetic polymorphisms, which seem to influence the pharmacokinetics of antiretroviral drugs, ultimately determining its efficacy and toxicity.

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Predictors of Virological Response to Atazanavir in Protease Inhibitor-Experienced Patients

Cited by 57 publications

References 12 publications

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

The Pharmacogenetics of HIV Treatment: A Practical Clinical Approach

Role of atazanavir in the treatment of HIV infection

Overview of the pharmacogenetics of HIV therapy

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