599 Impact of Amino-acid Insertions in HIV-1 p6 PTAP Region on the Virological Response to Amprenavir in the NARVAL Trial S. Lastere*1, C. Dalban2, G. Collin1, D. Descamps1, P.M. Girard3, F. Clavel4, D. Costagliola2, F. Brun-Vezinet1 1Bichat-Claude Bernard Hosp, Paris, France; 2INSERM EMI0214, Paris, France; 3St Antoine Hosp, Paris, France; and 4INSERM U552, Paris, France
Background: HIV protease (PR) evolution in response to antiretroviral (ARV) pressure can result in co-selection of mutations within Gag cleavage sites (CS). These mutations could be adaptive responses to reduced viral fitness and could play an important role in the resistance to PI. This study was aimed at evaluating the impact of the Gag CS mutations on the virological response to amprenavir (APV).
Methods: This study was performed in 82 highly ARV-experienced but APV-naive patients (pts), who were included in the NARVAL trial and receiving unboosted APV. Gag-protease fragments, including gag p2, p7, p1, p6, and whole PR, from baseline plasma samples were amplified and genotype was determined by population sequencing. The correlation between baseline Gag polymorphism, PR mutations, baseline characteristics, and virological response to APV (mean decrease in plasma viral load at week 12 :DeltaVL, log c/ml) was analyzed using Mann-Whitney or Kruskall-Wallis tests. To account for baseline characteristics and PR mutations, a multiple linear regression was used.
Results: Pts had median past exposure to 8 ARV drugs (5 nucleosides analogs and 3 PI). By wk 12, DeltaVL was of -0.99 ±1.19 log c/ml. At baseline, none of the pts had viruses with I50V APV specific mutation, and PR mutations at positions 10, 20, 36, 73, 82, 90 were individually associated (p < 0.2) with a poor virological response to APV, in univariate analysis. The majority of the pts exhibited an extensive polymorphism at CS. None of the published Gag CS mutations (A431V, n = 28 ; L449F, n = 7 ; P453L, n = 19) impacted the response to APV. Insertions at position 459 (P459Ins), involving the p6 PTAPP motif, were significantly associated with a decreased virological response (P459Ins, n = 14 versus wild-type, n = 68 : -0.3 ±0.8 log c/ml versus -1.1 ±1.2 log c/ml, p = 0.006) and were more frequent when the V82A/F/T/I PR mutation was present (p = 0.02). In multivariate analysis, the impact of P459Ins remained significant (p = 0.057) after adjustment on the predictive factors of the virological response in the NARVAL trial and on the PR mutations linked with response.
Conclusions: These results suggest that insertions in the p6 region of HIV-1 gag gene can affect the virological response, in highly pretreated pts receiving a unboosted APV containing regimen.
