17th International HIV Drug Resistance Workshop 10-14 June 2008, Sitges, Spain

IMPACT OF GAG MUTATIONS ON SELECTION OF DARUNAVIR RESISTANCE MUTATIONS IN HIV-1 PROTEASE
AG Marcelin¹, S Lambert-Niclot¹, A Canestri², C Soulie¹, M Wirden¹, R Tubiana², A Cheret³, C Katlama², P Flandre⁴ and V Calvez¹
Antivir Ther. 2008; 13(Suppl. 3):A51 (abstract no. 46)


¹Laboratoire de Virologie, Hôpital Pitié-Salpêtrière, Paris, France; ²Service des Maladies Infectieuses, Hôpital Pitié-Salpêtrière, Paris, France; ³Tibotec, France; ⁴INSERM U720, Paris, France

BACKGROUND: It has been shown in vitro that some protease inhibitors (PI) can select mutations in HIV gag comprising NC-P1/TFP-P6/P6*, without selecting mutations in the protease. Indeed, in vitro selection experiments using darunavir demonstrated phenotypic resistance that could not be explained by resistance mutation in the protease, but could be explained by gag mutations, including a cleavage site mutation at codon 437. Similar results have been found in vivo in isolates with gag mutations (at positions 431, 436 and 437) and which carried or did not carry known resistance mutations in the protease. The aim of this study was to search for genetic factors in the protease and gag regions (NC-P1/TFP-P6/P6*) involved in the selection of darunavir resistance mutations.

METHODS: Forty-eight PI-experienced HIV-infected patients suffering darunavir treatment failure were studied. Viral genotyping at baseline, month 3 and month 6 was used to assess the selection of mutations in the protease and gag regions. A gag–protease region of 323 bp, including the end of NC, P1/TFP and P6/P6* was amplified and sequenced. Darunavir mutations were defined according to International AIDS Society USA (IAS-USA) guidelines.

RESULTS: Patients received four PIs in median before darunavir. The median numbers of antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) used concurrently with darunavir were four, three and zero, respectively. There were no genotypic differences in the studied gag region between baseline and the latest available rebound isolates. There was an association between the presence of the mutation A431V in the gag sequence and the selection of the L76V mutation in the protease sequence in the latest available rebound. The I437T/V mutation in gag and the L76V mutation in the protease were associated with a lower risk of selecting other darunavir resistance mutations.

CONCLUSION: In these PI-treated patients suffering treatment failure of a darunavir-containing regimen, mutations in the gag region NC-P1/TFP-P6/P6* might influence the selection of darunavir resistance mutations; in particular, the I437T/V gag mutation that confers resistance to PI reduces the selection of darunavir resistance mutations in protease.

2008-06-10
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