Identification of I50L as the Signature Atazanavir (ATV)–Resistance Mutation in Treatment‐Naive HIV‐1–Infected Patients Receiving ATV‐Containing Regimens

Colonno, Richard J.; Rose, Ronald E.; McLaren, Colin; Thiry, Alexandra; Parkin, Neil; Friborg, Jacques

doi:10.1086/386291

Cited by 135 publications

(101 citation statements)

References 27 publications

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“…ATV may have an advantage over other PIs because of once-daily dosing, a distinct resistance profile, and a lack of insulin resistance and lipid increase. 6,7) With these advantages, ATV has been successfully used in treatment-native and -experienced HIV patients. 8) Similar to other PIs, however, ATV is poorly watersoluble and is known as a substrate of both a hepatic metabolizing enzyme, cytochrome P450 (CYP) 3A, and an intestinal drug efflux pump, P-glycoprotein (Pgp), thus resulting in low oral bioavailability (BA).…”

mentioning

confidence: 99%

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Fukushima

Haraya

Terasaka

et al. 2008

Biological & Pharmaceutical Bulletin

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The use of highly active antiretroviral therapy (HAART) has resulted in significant reductions in human immunodeficiency virus (HIV)-related mortality and morbidity, and transformed HIV disease to a chronic syndrome.1,2) Despite improved clinical outcomes with protease inhibitor (PI)-based HAART regimens, there are still many problems, such as high pill burden, resistance to antiretrovirals and metabolic abnormalities (e.g., hyperlipidemia, hyperglycemia). [3][4][5] Moreover, the transformation of HIV disease to a chronic syndrome also practically means that once patients start HAART, they should receive the drugs included in the HAART regimen for the rest of their life; therefore, not only long-term efficacy but also the safety of these drugs are of clinical significance.Atazanavir (ATV) is an azapeptide compound and the seventh addition to the family of HIV PIs. ATV may have an advantage over other PIs because of once-daily dosing, a distinct resistance profile, and a lack of insulin resistance and lipid increase.6,7) With these advantages, ATV has been successfully used in treatment-native and -experienced HIV patients.8) Similar to other PIs, however, ATV is poorly watersoluble and is known as a substrate of both a hepatic metabolizing enzyme, cytochrome P450 (CYP) 3A, and an intestinal drug efflux pump, P-glycoprotein (Pgp), thus resulting in low oral bioavailability (BA). 9) Clinically, to resolve this disadvantage, ATV is generally used with low-dose ritonavir (RTV) in the HAART regimen. RTV is also classified as a PI and is well known as a potent inhibitor of both CYP3A and Pgp. With this potent inhibition property, low-dose RTV has been demonstrated clinically to boost the BA of another concomitant PI. [10][11][12] HIV patients are typically treated with multiple drugs in addition to their HAART regimen. Hence, based on pharmacokinetic interaction, RTV-boosted HAART has great potential for drug-drug interactions with CYP3A and Pgp. 13,14) Moreover, it was also reported that RTV is not only a potent inhibitor but also a potent inducer of CYP3A and Pgp with chronic use. 15,16) This contradictory characteristic of RTV would further complicate drug-drug interactions and facilitate the clinical difficulties of HIV patients whose HIV infection must be controlled by RTV-boosted HAART. In addition, there are few studies on the effect of chronic use of lowdose RTV on its boosting effect and on pharmacokinetic interactions with concomitant drugs in addition to the HARRT regimen.We previously reported that the ATV pharmaceutical formulation, the physical mixture of Gelucire 50/13 and ATV solid dispersion in sodium lauryl sulfate (ATV-SLS SDϩG), could improve the BA of ATV without pharmacokinetic interaction with RTV.17) The aim of this study was to investigate the long-term efficacy and safety of RTV-boosted ATV and ATV-SLS SDϩG and to directly compare both formulations; therefore, we administered RTV-boosted ATV or ATV-SLS SDϩG for 14 d to rats and compared the pharmacoki- Atazanavir (ATV) is clinically coadminis...

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confidence: 99%

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Fukushima

Haraya

Terasaka

et al. 2008

Biological & Pharmaceutical Bulletin

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“…This substitution conferring resistance to Atazanavir is characteristic of PI-naive patients, but is very rare in pretreated patients (Noor et al, 2006). Comparison of viruses bearing I50L with those bearing I50V revealed specific resistance to Atazanavir and Amprenavir (APV), respectively, with no evidence of cross-resistance (Colonno et al, 2004;Weinheimer et al, 2005). The HIV-protease enzyme from multi-experienced subjects is already largely mutated and therefore considerably stiff, one of the reasons for the rarity of mutation I50L in subjects who have accumulated multiple resistances to PIs.…”

Section: Discussionmentioning

confidence: 99%

Evolution of the HIV-1 protease region in heavily pretreated HIV-1 infected patients receiving Atazanavir

Vergani

Cicero

Viganò

et al. 2008

Journal of Clinical Virology

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Background: Previous in vitro studies indicated that Atazanavir (ATV) has a distinct resistance profile than other protease inhibitors (PIs). In treatment-experienced patients ATV resistance is characterised by the accumulation of at least four mutations among those that confer cross-resistance to the PIs. Objective: We studied the evolution of PIs resistance mutations in 10 HAART-failed patients undergoing ATV enrolled in an early access program. Study design: Virus genotypic resistance was determined from plasma collected at baseline and during treatment. HIV-RNA was extracted and the pol region amplified and sequenced. Genotypic data were used to determine drug susceptibility. Phylogenetic analysis was performed. Results: At baseline, genotypic data showed cross-resistance patterns to approved PIs in 6 patients. In two of these subjects new mutations (I54V and A71V) conferring cross-resistance emerged after 3 months of therapy. The I50L mutation was evidenced in one subject after 12 months of treatment. The "virtual" phenotype analysis mirrored the resistance profiles to ATV and other PIs and evidenced differences with tipranavir and darunavir. Conclusion: Genotype evolution within the protease region did not emerge at significant levels during salvage therapy of multidrug-experienced patients. ATV exhibited certain/same virologic effect on the majority of our patients.

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“…Winters et al, 2008). Similarly; I50L, I84 and N88S mutations are associated with high levels of phenotypic resistance to atazanavir/r (Colonno et al, 2004;Pellegrin et al, 2006;Rhee et al, 2006b;Vermeiren et al, 2007;Vora et al, 2006;B. Winters et al, 2008).…”

Section: Point Mutations Associated With Resistance To Protease Inhibmentioning

confidence: 99%

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

Khati¹,

Millroy²

2012

Point Mutation

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Identification of I50L as the Signature Atazanavir (ATV)–Resistance Mutation in Treatment‐Naive HIV‐1–Infected Patients Receiving ATV‐Containing Regimens

Cited by 135 publications

References 27 publications

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Long-Term Pharmacokinetic Efficacy and Safety of Low-Dose Ritonavir as a Booster and Atazanavir Pharmaceutical Formulation Based on Solid Dispersion System in Rats

Evolution of the HIV-1 protease region in heavily pretreated HIV-1 infected patients receiving Atazanavir

Point Mutations Associated with HIV-1 Drug Resistance, Evasion of the Immune Response and AIDS Pathogenesis

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