Mutations associated with virological response to darunavir/ritonavir in HIV-1-infected protease inhibitor-experienced patients

Abstract

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/mm 3. 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 witha 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. © The Author 2009. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.