Virological Responses to Atazanavir–Ritonavir-Based Regimens: Resistance-Substitutions Score and Pharmacokinetic Parameters (Reyaphar Study)

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Abstract
Objective: To assess the impact of baseline HIV-1 substitutions, individual pharmacokinetic (PK) parameters (Cmin, Cmax, area under the curve [AUC0→24 h]) and genotype-inhibitory quotient (GIQ) on virological responses (VR) to atazanavir-ritonavir (300 mg/100 mg)-based highly active antiretroviral therapy (HAART) in 71 antiretroviral-experienced, atazanavir-naive patients in virological failure (VF) on HAART. Methodology: VR was defined as HIV RNA 10 copies/ml at week 12 (W12). A clinically relevant genotype-substitutions score for atazanavir-ritonavir was developed and validated (Reyaphar substitutions score). Previously published substitutions scores were also tested. Results: Patients had a median (Q1; Q3) of 6 (3; 8) previous treatment lines during 9 (7; 11) years. Baseline (W0) values were as follows: 262 (187; 435) CD4+/μl, 3.9 (2.6; 4.9) log10 HIV-1 RNA copies/ml, 4 (2; 6) protease substitutions and 3 (1; 4) NRTI-related substitutions. Respective steady-state Cmin, Cmax and AUC0→24h were 300 (200; 700) ng/ml, 620 (430; 750) ng/ml and 78,000 (61,000; 94,000) ng.h/ml. At W12, 49% of the patients had VR with a median decrease of -1.2 (-0.5; -2.3) log10 HIV-1 RNA copies/ml. The Reyaphar score included 12 baseline protease substitutions from the International AIDS Society USA list that were associated with poorer VR: L10I/F/R/V, K20I/M/R, L24I, M46I/L, I54L/M/T/V, L63P, A71I/L/V/T, G73A/C/F/T, V77I, V82A/F/S/T, I84V, L90M and the polymorphism substitution Q58E. Comparing 12-W0 HIV-1 RNA decrease was -1.4 (-0.7; -2.3) versus -0.5 (-1.2; +0.5) log10 copies/ml ( P=0.009) with VR in 63% versus 11% ( P4), respectively. This score predicted VF at W12 with 46% sensitivity, compared to 33% and 28% for the ANRS 2004 and 2005 scores. PK parameters alone were not associated with VR, but GIQ was associated with virological outcome ( P=0.04). I50L, known to be correlated with atazanavir-specific resistance, emerged in 2 (8%) of the 24 failing patients with paired genotypes at W0 and VF. Conclusions: These findings highlight the need to cross-validate genotype-based algorithms to interpret substitution impact on virological outcome using different patient databases before their implementation in routine clinical practice.

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