Gag mutations can impact virological response to dual-boosted protease inhibitor combinations in antiretroviral-naïve HIV-infected patients

Abstract

ANRS 127 was a randomized pilot trial involving naïve patients receiving two dual-boosted protease inhibitor (PI) combinations. Virological response, defined as a plasma HIV RNA level of <50 copies/ml at week 16, occurred in only 41% patients. Low baseline plasma HIV RNA level was the only significant predictor of virological response. The purpose of this study was to investigate the impact on virological response of pretherapy mutations in cleavage sites of gag, gag-pol, and the gag-pol frameshift region. The whole gag gene and protease-coding region were amplified and sequenced at baseline and at week 16 for 48 patients still on the allocated regimen at week 16. No major PI resistance-associated mutations were detected either at baseline or in the 26 patients who did not achieve virological response at week 16. Baseline cleavage site substitutions in the product of the gag open reading frame at positions 128 (p17/p24) (P = 0.04) and 449 (p1/p6(gag)) (P = 0.01) were significantly more frequent in those patients not achieving virological response. Conversely, baseline cleavage site mutation at position 437 (TFP/p6(pol)) was associated with virological response (P = 0.04). In multivariate analysis adjusted for baseline viral load, these 3 substitutions remained independently associated with virological response. We demonstrated here, in vivo, an impact of baseline polymorphic gag mutations on virological response in naïve patients receiving a combination of two protease inhibitors. However, it was not possible to link the substitutions selected under PI selective pressure with virological failure.

FIG. 1.

Percentages of patients among the 48 PI-treated patients with baseline gag and gag-pol cleavage site (CS) mutations compared to the HXB2 reference sequence in the product of the gag open reading frame according to virological response at week 16 (W16). There were 22 patients with plasma HIV-1 RNA levels below 50 copies/ml and 26 patients with plasma HIV-1 RNA levels above 50 copies/ml at W16. For the gag open reading frame: (A) CS p17/p24; (B) CS p24/p2; (C) CS p2/p7; (D) CS p7/p1; and (E) CS p1/p6^gag. For the gag-pol open reading frame: (F) CS TFP/p6^pol and (G) p6^pol C terminus. c/ml, copies/ml; del, deletion; ins, insertion; PR, protease; TFP, transframe protein.

FIG. 2.

HIV-1 protease amino acid bulk sequences at baseline and at week 16 (W16) for all patients with plasma HIV-1 RNA levels above 50 copies/ml at week 16 (identified here as patients 1 to 26). HXB2 was the reference strain.

FIG. 3.

Proportions of mutations in HIV-1 in the products of the gag and gag-pol open reading frames at baseline for B and non-B subtypes.