[8] VIROLOGICAL RESPONSE TO ATAZANAVIR/RITONAVIR-BASED REGIMENS: RESISTANCE MUTATIONS SCORE AND PHARMACOKINETIC PARAMETERS (Cmin, Cmax, AUC) (REYAPHAR STUDY)

14th International HIV Drug Resistance Workshop

7-11 June 2005, Québec City, Canada

VIROLOGICAL RESPONSE TO ATAZANAVIR/RITONAVIR-BASED REGIMENS: RESISTANCE MUTATIONS SCORE AND PHARMACOKINETIC PARAMETERS (C_min, C_max, AUC) (REYAPHAR STUDY)

Antivir Ther. 10, Suppl 1:S10 (abstract 8)

I Pellegrin¹, M Vray², D Neau³, HJA Fleury¹, MH Schrive¹, M-C Saux⁴, J-L Pellegrin³, E Lazaro³, J-M Ragnaud³, D Breilh⁴
¹Department of Virology; ²Institut Pasteur Emerging Diseases Epidemiology Unit; ³Internal Medicine and Infectious Diseases; ⁴Pharmacy, Bordeaux University Hospital, Bordeaux, and Paris, France

OBJECTIVE: The aim of this study was to assess the impact of HIV-1 mutations, individual PK parameters (C_min, C_max, AUC) and genotypic inhibitory quotient (GIQ) on virological responses to atazanavir/ritonavirbased regimens in experienced HIV patients.

METHODS: Antiretroviral-experienced subjects with virological failure (HIV-RNA>1.7 log₁₀ copies/ml) were included in an observational cohort study and received an atazanavir/ritonavir (300 mg/100 mg)- based HAART. Sequencing of HIV-reverse-transcriptase and protease was performed at baseline. Virological success (VS) was defined by HIV- RNA<1.7 log₁₀ copies/ml at 6 months. Atazanavir C_min, C_max and AUC were determined at steady-state using a population PK analysis. GIQ was calculated with C_min/number of atazanavir/ritonavir resistance-related mutations among L10F/I/V,K20I/M/ R,L24I,L33F/I/V,M36I/L/V,M46I/L,G48V,I54L/V,L63 P,A71I/V/T,G73A/C/S/T,V82A/F/T/S,I84V,L90M (French ANRS genotype-interpretation guidelines).

RESULTS: Atazanavir/ritonavir-containing regimen was initiated in 90 patients (M/F=63/27, median [25^th–75^th] age=45 [40;52]), in association with tenofovir+ lamivudine or emtricitabine in 60% of them. Patients were antiretroviral-experienced: PI=91%, NNRTI=62% (80% of whom with NNRTI-related mutations), five [two to seven] previous treatment lines, 9 [5–10] years of treatment. At baseline, median CD4+ and HIV-1-RNA were 273 [196–473]/µl and 3.9 [2.7–4.7] log₁₀ copies/ml, respectively. Median number of atazanavir/ritonavir resistance-related mutations was two [one to four] and three [zero to four] NRTI-related mutations. C_min, C_max, AUC and GIQ were 0.4 [0.2;0.8] µg/ml, 6.2 [5.1;7.4] µg/ml, 80 [64;95] mg.h/l and 0.13 [0.07;0.4], respectively. At M6, median HIV-1-RNA decrease was -1.2 [-2.8;- 0.3] log₁₀ copies/ml, CD4 increase was +51 [-8;+174] and 66% of patients were considered VS. When atazanavir score was <6 versus ≥6 mutations, HIV-1- RNA decrease was -1.74 [-2.8;-0.4] versus +0.01 [- 1;+0.3] log₁₀ copies/ml (P=0.01) and VS occurred in 75% versus 20% (P=0.002), respectively. When GIQ was <0.13 versus >0.13, VS occurred in 50% versus 80% of patients, respectively (P=0.027). In univariate analysis, failure was associated with baseline number of protease and reverse-transcriptase mutations (P=3.10^-3, P<10^-4), atazanavir/ritonavir score (P<10^-4). Presence of following protease mutations at baseline were associated with failure: L10I, K20R, M46I/L, 54L/T/V, L90M. Pharmacokinetics parameters alone were not associated with virological outcome (C_min (P=0.41), C_max (P=0.47), AUC (P=0.52)), whereas GIQ was associated with VS (P=0.03).

CONCLUSION: Monitoring of atazanavir/ritonavirbased HAART should take into account both number of baseline atazanavir/ritonavir resistance-related mutations (<6 versus ≥6) and GIQ.

PRESENTING AUTHOR: I Pellegrin

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2005-06-07
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