Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors

Colonno, Richard J.; Thiry, Alexandra; Limoli, Kay; Parkin, Neil

doi:10.1128/aac.47.4.1324-1333.2003

Cited by 89 publications

(70 citation statements)

References 33 publications

(33 reference statements)

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“…1 As measure of potency, the concentration that inhibits 50% of viral replication (IC50) in the absence of human serum ranged from 0.58 ng/mL to 5.7 ng/mL in a panel of susceptible viruses isolated from 31 PI-naïve HIV-infected patients. 2,3 The presence of 40% human serum in cell cultures increased ATV IC50 by 2.7-to 3.6-fold, as noticed for other PIs. The adjusted IC50 for protein binding was estimated to range from 8 to 20 ng/mL against reference viral strains with a conventional cycle cell infection and the PhenoSense TM single assay (ViroLogic Inc., South San Francisco, CA, USA), respectively.…”

Section: Mechanism Of Actionsupporting

confidence: 55%

“…In vitro analysis of the genotypic profi les of 943 PI-susceptible and PI-resistant clinical isolates identifi ed a strong correlation between the presence of several amino acid changes at specifi c residues (10I/V/F, 20R/M/I, 24I, 33I/F/V, 36I/L/V, 46I/L, 48V, 54V/L, 63P, 71V/T/I, 73C/S/T/A, 82A/F/S/T, 84V, and 90M) and decreased susceptibility to ATV. 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.…”

Section: Drug Resistancementioning

confidence: 99%

“…2 The NADIS French study proved that ATV/r-based rescue therapy is generally effi cient in most PI-experienced patients, except in those who had failed an LPV/r-containing regimen.…”

Section: Cross-resistancementioning

confidence: 99%

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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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Section: Mechanism Of Actionsupporting

confidence: 55%

Section: Drug Resistancementioning

confidence: 99%

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Role of atazanavir in the treatment of HIV infection

Soriano¹

2008

TCRM

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“…Earlier in vitro studies demonstrated that the substitutions M46I, A71V, N88S, I84V, and I50L, which were identified in laboratory strains of PRT variants selected against atazanavir, may play important roles in the resistance phenotype and that multiple mutational pathways can lead to resistance (17). In clinical studies of treatment-experienced patients who received atazanavir-containing regimens, a reduction in atazanavir susceptibility required combinations of several amino acid substitutions (7). High levels of atazanavir resistance were observed only with HIV isolates cross-resistant to all approved PIs, and these viruses were characterized by the accumulation of several mutations (M46I, I84V, N88S/D, and L90M).…”

mentioning

confidence: 99%

“…The loss of PRT susceptibility of viral isolates with the IRM mutations to the approved PIs, atazanavir included, varied between 7-and 71-fold (17). The M46I and L90M substitutions were associated with atazanavir resistance in clinical studies (7). Furthermore, the V82F and I84V subset, especially when present in tandem, has been shown to adversely affect PRT susceptibility (17,23,55).…”

mentioning

confidence: 99%

X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

Klei

Kish

Lin

et al. 2007

J Virol

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Atazanavir, which is marketed as REYATAZ, is the first human immunodeficiency virus type 1 (HIV-1) protease inhibitor approved for once-daily administration. As previously reported, atazanavir offers improved inhibitory profiles against several common variants of HIV-1 protease over those of the other peptidomimetic inhibitors currently on the market. This work describes the X-ray crystal structures of complexes of atazanavir with two HIV-1 protease variants, namely, (i) an enzyme optimized for resistance to autolysis and oxidation, referred to as the cleavage-resistant mutant (CRM); and (ii) the M46I/V82F/I84V/L90M mutant of the CRM enzyme, which is resistant to all approved HIV-1 protease inhibitors, referred to as the inhibitor-resistant mutant. In these two complexes, atazanavir adopts distinct bound conformations in response to the V82F substitution, which may explain why this substitution, at least in isolation, has yet to be selected in vitro or in the clinic. Because of its nearly symmetrical chemical structure, atazanavir is able to make several analogous contacts with each monomer of the biological dimer.The human immunodeficiency virus type 1 (HIV-1) protease (PRT) enzyme is essential for viral replication. As such, it is an attractive target for antiviral therapy. Indeed, a sustained, international effort of structure-based drug design has led to the development of potent HIV-1 PRT inhibitors (PIs) that bind to the active site of mature PRT. Several of these drugs are currently in use for the treatment of AIDS (18,31,36). The seven FDA-approved PIs currently on the market (in order of approval [http://www.fda.gov/oashi/aids/virals.html])-saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, and atazanavir-are competitive peptidomimetics (10,15). Unfortunately, the use of these PIs can lead to rapid selection for drug-resistant PRT variants (1,42,50). Mutations of the conserved PRT residues V82, I84, and L90 are among those most commonly observed in patients receiving PI-containing regimens. In addition, the collective data from clinical failures of antiviral therapy show considerable cross-resistance among the PIs (19). Both factors threaten the long-term effectiveness of these drugs. Therefore, it is important to understand the mechanisms that govern drug resistance in order to develop more effective inhibitors and to rationally formulate drug regimens.Atazanavir, a highly potent azapeptide, is the most recently approved HIV-1 PI. A favorable pharmacokinetic profile allows once-daily dosing (37,43,47). More importantly, atazanavir has a distinct resistance profile relative to those of the other approved PIs. Earlier in vitro studies demonstrated that the substitutions M46I, A71V, N88S, I84V, and I50L, which were identified in laboratory strains of PRT variants selected against atazanavir, may play important roles in the resistance phenotype and that multiple mutational pathways can lead to resistance (17). In clinical studies of treatment-experienced patients who received atazanavir-c...

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TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

Ghosh

Anderson

Mitsuya

2010

Burger's Medicinal Chemistry and Drug Discovery

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Over the past two decades, HIV protease inhibitors have helped revolutionize the treatment of HIV/AIDS transforming this deadly ailment into a more manageable chronic infection. Due to intensive research in the area, a variety of protease inhibitors are now commercially available each of which possesses distinct characteristics and a unique tale of discovery. This manuscript reviews the design and development of the 10 currently available protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir, and darunavir. Special attention is given to the research efforts leading to their discovery and the successes and limitations of these drugs in the clinics. A brief review of the biology associated with the HIV‐1 protease target is provided in addition to a discussion of novel drug candidates currently under investigation.

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Activities of Atazanavir (BMS-232632) against a Large Panel of Human Immunodeficiency Virus Type 1 Clinical Isolates Resistant to One or More Approved Protease Inhibitors

Cited by 89 publications

References 33 publications

Role of atazanavir in the treatment of HIV infection

Role of atazanavir in the treatment of HIV infection

X-Ray Crystal Structures of Human Immunodeficiency Virus Type 1 Protease Mutants Complexed with Atazanavir

TheFDAApprovedHIV‐1 Protease Inhibitors for Treatment ofHIV/AIDS

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