Two Different Patterns of Mutations Are Involved in the Genotypic Resistance Score for Atazanavir Boosted Versus Unboosted by Ritonavir in Multiple Failing Patients

Overview

Journal Infection

Date 2009 Jan 27

PMID 19169632

Citations 5

Authors

M M Santoro

A Bertoli

P Lorenzini

F Ceccherini-Silberstein

N Gianotti

C Mussini

C Torti

G Di Perri

G Barbarini

T Bini

S Melzi

P Caramello

R Maserati

P Narciso

V Micheli

A Antinori

C F Perno

Affiliations

Soon will be listed here.

Abstract

Objectives: The protease inhibitor atazanavir (ATV) can be used either boosted by ritonavir (ATV300/r) or unboosted (ATV400). To date, however, genotypic resistance scores (GRSs) have been developed only for boosted-ATV. We have determined GRS associated with virologic response (VR) for both ATV300/r and ATV400 in highly pre-treated HIV-1 infected patients.

Patients And Methods: We analyzed the results of genotypic tests available 0-3 months before the initiation of an ATV-containing regimen in 159 patients with HIV-RNA >or= 500 copies/ml (ATV300/r group: 74; ATV400 group: 85) who were enrolled in the CARe study through an Early Access Program. The impact of baseline protease mutations on VR (>or= 1 log(10)copies/ml HIV-RNA decrease at 12-24 weeks) was analyzed using Fisher's exact test. Mutated protease amino acid positions (MPP) with p < 0.20 were retained for further analysis. The GRSs were determined by a step-by-step analysis using the chi(2) test for trend.

Results: The GRSs for ATV300/r and ATV400 revealed differing sets of mutations. For ATV300/r, 12 MPPs (10C/I/V + 32I + 34Q + 46I/L + 53L + 54A/M/V + 82A/F/I/T + 84V + 90M - 15E/G/L/V - 69K/M/N/Q/R/T/Y - 72M/ T/V; p = 1.38 x 10(-9)) were the most strongly associated with VR (VR: 100%, 78.3%, 83.3%, 75% and 0% of patients with a score of -2/-1, 0, 1, 2, and >or= 3, respectively); the last three MPPs (I15/H69/I72) were associated with a better VR. For ATV400, nine MPPs (16E + 20I/M/R/T/V + 32I + 33F/I/V + 53L/Y + 64L/M/ V + 71I/T/V + 85V + 93L/M; p = 9.42 x 10(-8)) were most strongly associated with VR (VR: 83.3%, 66.7%, 5.9%, 0% of patients with 0, 1/2, 3, and >or= 4 MPP, respectively). Differences between GRSs for ATV300/r and ATV400 may be due to different ATV drug levels (boosted vs unboosted), favoring different pathways of escape from antiviral pressure.

Conclusions: Both GRSs were independent predictors of response in a multivariable logistic regression model. Nevertheless, cross-validation of these GRSs on different patient databases is required before their implementation in clinical practice.

Citing Articles

Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study.

Dolling D, Dunn D, Sutherland K, Pillay D, Mbisa J, Parry C J Antimicrob Chemother. 2013; 68(10):2339-43.

PMID: 23711895 PMC: 3772741. DOI: 10.1093/jac/dkt199.

Genotypic resistance profiles associated with virological failure to darunavir-containing regimens: a cross-sectional analysis.

Sterrantino G, Zaccarelli M, Colao G, Baldanti F, Di Giambenedetto S, Carli T Infection. 2012; 40(3):311-8.

PMID: 22237471 DOI: 10.1007/s15010-011-0237-y.

Long-term treatment of patients with HIV-1: the role of atazanavir.

Artacho M, Barreiro P, Fernandez-Montero J HIV AIDS (Auckl). 2011; 2:157-66.

PMID: 22096394 PMC: 3218682. DOI: 10.2147/HIV.S5069.

Co-lethality studied as an asset against viral drug escape: the HIV protease case.

Brouillet S, Valere T, Ollivier E, Marsan L, Vanet A Biol Direct. 2010; 5:40.

PMID: 20565756 PMC: 2898770. DOI: 10.1186/1745-6150-5-40.

Role of atazanavir in the treatment of HIV infection.

Rivas P, Morello J, Garrido C, Rodriguez-Novoa S, Soriano V Ther Clin Risk Manag. 2009; 5(1):99-116.

PMID: 19436623 PMC: 2697529.

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