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


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 log(10) 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 log(10) 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.
Descamps
Diane
D
AP-HP, Groupe Hospitalier Bichat-Claude Bernard and Université Denis Diderot-Paris 7, Laboratoire de Virologie, Paris, France. diane.descamps@bch.aphp.fr
Lambert-Niclot
Sidonie
S
Marcelin
Anne-Geneviève
AG
Peytavin
Gilles
G
Roquebert
Bénédicte
B
Katlama
Christine
C
Yeni
Patrick
P
Felices
Mathieu
M
Calvez
Vincent
V
Brun-Vézinet
Françoise
F
D019943:Amino Acid Substitution / Q000235:genetics; D018791:CD4 Lymphocyte Count; D000069454:Darunavir; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000821:virology; D016333:HIV Protease / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000627:therapeutic use*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D012367:RNA, Viral / Q000097:blood; D019438:Ritonavir / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome; D019562:Viral Load
D017320:HIV Protease Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; D019438:Ritonavir; D000069454:Darunavir