JAC Advance Access originally published online on January 15, 2009
Journal of Antimicrobial Chemotherapy 2009 63(3):585-592; doi:10.1093/jac/dkn544
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Original research |
Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients
1 AP-HP, Groupe hospitalier Bichat-Claude Bernard and Université Denis Diderot-Paris 7, Laboratoire de Virologie, Paris, France 2 AP-HP, Groupe hospitalier Pitié-Salpêtrière and UPMC Univ 06 UMR_S 943, Service de Virologie, Paris, France 3 SGS, Aster, S.A.S, Paris, France 4 AP-HP, Groupe hospitalier Pitié-Salpêtrière and UPMC Univ 06 UMR_S 943, Service de Maladies Infectieuses et Tropicales, Paris, France 5 AP-HP, Groupe hospitalier Bichat-Claude Bernard and Université Denis Diderot-Paris 7, Service de Maladies Infectieuses et Tropicales, Paris, France
Received 6 October 2008; returned 12 November 2008; revised 8 December 2008; accepted 17 December 2008
* Corresponding author. Laboratoire de Virologie, Bichat Claude Bernard Hospital, 46 rue Henri Huchard, 75877 Paris cedex 18, France. Tel: +33-140256150; Fax: +33-140256769; E-mail: diane.descamps{at}bch.aphp.fr
Objective: The aim of the study was to identify a pattern of protease gene mutations associated with the virological response to darunavir/ritonavir-based regimens.
Patients and methods: We analysed 153 treatment-experienced patients receiving a darunavir/ritonavir salvage regimen as a sole protease inhibitor (PI). Virological response was defined as an HIV-1 RNA load of <200 copies/mL at month 3. The impact of individual protease gene mutations on the virological response to darunavir/ritonavir was examined, and the combination of mutations most strongly associated with the virological response was identified.
Results: The baseline median HIV RNA level was 4.7 log10 copies/mL and the median CD4 cell count was 142 cells/mm3. At month 3, 55% of patients had a virological response and the median fall in viral load from baseline was 1.7 log10 copies/mL. All the patients had detectable darunavir concentrations at month 3. Cochran–Armitage procedure identified eight mutations with a negative impact on the virological response, namely K14R, K20I, E34Q, I47V, I54M, K55R, T74P and I84V; and two mutations (E35D and V82A) with a positive impact. In multivariate analyses, our genotypic scores were highly predictive of the virological response at month 3, along with the baseline plasma viral load and enfuvirtide co-prescription to enfuvirtide-naive patients.
Conclusions: Among the eight mutations with a negative impact on the virological response, I47V, I54M, T74P and I84V were previously described as darunavir resistance-associated mutations. Some PI resistance mutations had a positive impact on the virological response. These findings might help to explain the potency of darunavir/ritonavir on PI-resistant HIV.
Keywords: resistance , genotypic score , genotype interpretation